|
1
|
Sun Y, Yuan X, Hu Z, Li Y. Harnessing nuclear receptors to modulate hepatic stellate cell activation for liver fibrosis resolution. Biochem Pharmacol 2025; 232:116730. [PMID: 39710274 DOI: 10.1016/j.bcp.2024.116730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 12/04/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis. Therefore, harnessing nuclear receptors to modulate HSC activation may be an effective approach to resolving the complex liver fibrosis caused by various factors. In this comprehensive review, we systematically explore the structure and physiological functions of nuclear receptors, shedding light on their multifaceted roles in HSC activation. Recent advancements in drug development targeting nuclear receptors are discussed, providing insights into their potential as rational and effective therapeutic targets for modulating HSC activation in the context of liver fibrosis. By elucidating the intricate interplay between nuclear receptors and HSC activation, this review contributes to the discovery of new nuclear receptor targets in HSCs for resolving hepatic fibrosis.
Collapse
Affiliation(s)
- Yaxin Sun
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoyan Yuan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhenhua Hu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; Department of Health and Nursing, Nanfang College of Sun Yat-sen University, Guangzhou, China.
| | - Yuanyuan Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
2
|
Yi S, Mai T, Fang Y, Tian Q, Zhao S. Repeated Injection of Xylazine Causes Liver Injury Through the PPAR Signaling Pathway in Rats. J Biochem Mol Toxicol 2025; 39:e70101. [PMID: 39692361 DOI: 10.1002/jbt.70101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 11/20/2024] [Accepted: 12/07/2024] [Indexed: 12/19/2024]
Abstract
With the gradual emergence of xylazine as a street drug, incidents of xylazine poisoning are now occurring worldwide. However, it remains unknown whether long-term exposure to xylazine causes nonalcoholic fatty liver disease (NAFLD). In the present study, the rats were injected with xylazine intraperitoneally for 28 consecutive days, and then serum and liver tissues were collected for analysis. Weight loss was observed in the 40 mg/kg group and elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed. Histopathologic examination showed hepatic steatosis, necrosis, and fibrosis. By mRNA sequencing, 192 upregulated genes and 277 downregulated genes were found in the 40 mg/kg group, and the PPAR signaling pathway was ranked first in the KEGG pathway analysis. Four genes in the PPAR signaling pathway, Fabp5, Acox2, and Cpt2, were also verified in the 40 mg/kg group by RT-qPCR analysis and western blot. Our results demonstrated that long-term injection of xylazine causes NAFLD and the PPAR signaling pathway plays a core role in the process of xylazine-associated liver injury.
Collapse
Affiliation(s)
- Shanyong Yi
- Xinxiang Key Laboratory of Forensic Toxicology, School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, China
| | - Tingting Mai
- Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Guangzhou, Guangdong, China
| | - Ying Fang
- Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Guangzhou, Guangdong, China
| | - Qishuo Tian
- Health Sciences Education Department, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shuquan Zhao
- Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Guangzhou, Guangdong, China
| |
Collapse
|
|
3
|
Gilgenkrantz H, Paradis V, Lotersztajn S. Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma. Hepatology 2025; 81:269-287. [PMID: 37212145 PMCID: PMC11643143 DOI: 10.1097/hep.0000000000000479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/21/2023] [Indexed: 05/23/2023]
Abstract
Progression of chronic liver injury to fibrosis, abnormal liver regeneration, and HCC is driven by a dysregulated dialog between epithelial cells and their microenvironment, in particular immune, fibroblasts, and endothelial cells. There is currently no antifibrogenic therapy, and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and nonparenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach. In this review, we discuss how modulating intrinsic metabolism of key effector liver cells might disrupt the pathogenic sequence from chronic liver injury to fibrosis/cirrhosis, regeneration, and HCC.
Collapse
Affiliation(s)
- Hélène Gilgenkrantz
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
| | - Valérie Paradis
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
- Pathology Department, Beaujon Hospital APHP, Paris-Cité University, Clichy, France
| | - Sophie Lotersztajn
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
| |
Collapse
|
|
4
|
Wu H, Wu L, Luo L, Wu YT, Zhang QX, Li HY, Zhang BF. Quercetin inhibits mitophagy-mediated apoptosis and inflammatory response by targeting the PPARγ/PGC-1α/NF-κB axis to improve acute liver failure. Int Immunopharmacol 2024; 143:113444. [PMID: 39454407 DOI: 10.1016/j.intimp.2024.113444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/07/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND Reactive oxygen species (ROS) from mitochondrial dysfunction are critical in triggering apoptosis and inflammation in acute liver failure (ALF). Quercetin (QUE), an antioxidant, is renowned for its therapeutic effects onliverdiseases. There are no studies on whether QUE regulates mitophagy level in hepatocytes to inhibit ALF. OBJECTIVE This study investigates QUE's protective effects on ALF and elucidates the mechanisms involved. METHODS The ALF and hepatocyte inflammatory injury model was established using LPS and D-Galn. To predict potential targets and mechanisms of QUE in ALF treatment, transcriptomics, network pharmacology, molecular docking techniques, and ChIP were employed. The expression level related to mitophagy, apoptosis, and signaling pathways were detected by CCK8, IHC, IF staining, TUNEL, RT-qPCR, TEM, Western blotting, ELISA, and flow cytometry. RESULTS Network pharmacology and transcriptomics revealed common targets between QUE and ALF. Enrichment analysis showed that the anti-ALF targets of QUE were significantly associated with mitochondria and NF-κB-related pathways. Subsequent experiments showed that QUE pretreatment significantly alleviated the loss of hepatocyte viability, enhanced mitochondrial membrane potential, activated mitophagy, and promoted the clearance of damaged mitochondria, thereby reducing ROS accumulation, significantly reducing cell apoptosis and inflammatory responses, reducing ALT and AST levels, and improving liver tissue pathology. Mechanistically, molecular docking, DARTS, and CETSA analyses confirmed that QUE directly binds to the PPARγ molecule, which reduced binding to IκB and significantly inhibit the NF-κB pathway to exert its protective effects. CONCLUSION In short, our results provide the first evidence that QUE improves acute liver failure by promoting mitophagy through regulating the PPARγ/PGC-1α/NF-κB axis and inhibiting apoptosis and inflammatory responses mediated by mitochondrial dysfunction, which provides evidence for the potential of QUE in the treatment of ALF.
Collapse
Affiliation(s)
- Huan Wu
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Long Wu
- Department of Anus and Intestinal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Li Luo
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Ye-Ting Wu
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Qing-Xiu Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Hai-Yang Li
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Bao-Fang Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
| |
Collapse
|
|
5
|
Aibara D, Sakaguchi A, Matsusue K. Transmembrane and coiled-coil domain family 3 gene is a novel target of hepatic peroxisome proliferator-activated receptor γ in fatty liver disease. Mol Cell Endocrinol 2024; 594:112379. [PMID: 39326649 DOI: 10.1016/j.mce.2024.112379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 09/19/2024] [Accepted: 09/24/2024] [Indexed: 09/28/2024]
Abstract
The peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor abundantly expressed in the nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the mechanism by which PPARγ regulates the transmembrane and coiled-coil domain family 3 (Tmcc3) gene in the liver. We found that TMCC3 is highly expressed in the fatty liver of humans and mice with NAFLD and alcoholic fatty liver disease. Three exon 1 variants (Tmcc3-1a, -1b, and -1c) of mouse Tmcc3 were identified. TMCC3-1B was highly expressed in the fatty liver of type 2 diabetic ob/ob mice; however, this increase in expression was ameliorated by liver-specific knockout of PPARγ. Reporter assays and electrophoretic mobility shift assays showed that PPARγ positively regulates Tmcc3-1b and -1c transcription through the same PPARγ-responsive element present in the 5'-region of each Tmcc3. Altogether, our results indicate that Tmcc3 is a novel PPARγ target in the fatty liver disease.
Collapse
Affiliation(s)
- Daisuke Aibara
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Ai Sakaguchi
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Kimihiko Matsusue
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
| |
Collapse
|
|
6
|
Chakraborty S, Anand S, Bhandari RK. Medaka liver developed Human NAFLD-NASH transcriptional signatures in response to ancestral bisphenol A exposure. RESEARCH SQUARE 2024:rs.3.rs-4585175. [PMID: 39070641 PMCID: PMC11275980 DOI: 10.21203/rs.3.rs-4585175/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
The progression of fatty liver disease to non-alcoholic steatohepatitis (NASH) is a leading cause of death in humans. Lifestyles and environmental chemical exposures can increase the susceptibility of humans to NASH. In humans, the presence of bisphenol A (BPA) in urine is associated with fatty liver disease, but whether ancestral BPA exposure leads to the activation of human NAFLD-NASH-associated genes in the unexposed descendants is unclear. In this study, using medaka fish as an animal model for human NAFLD, we investigated the transcriptional signatures of human NAFLD-NASH and their associated roles in the pathogenesis of the liver of fish that were not directly exposed, but their ancestors were exposed to BPA during embryonic and perinatal development three generations prior. Comparison of bulk RNA-Seq data of the liver in BPA lineage male and female medaka with publicly available human NAFLD-NASH patient data revealed transgenerational alterations in the transcriptional signature of human NAFLD-NASH in medaka liver. Twenty percent of differentially expressed genes (DEGs) were upregulated in both human NAFLD patients and medaka. Specifically in females, among the total shared DEGs in the liver of BPA lineage fish and NAFLD patient groups, 27.69% were downregulated, and 20% were upregulated. Of all DEGs, 52.31% of DEGs were found in ancestral BPA-lineage females, suggesting that NAFLD in females shared the majority of human NAFLD gene networks. Pathway analysis revealed beta-oxidation, lipoprotein metabolism, and HDL/LDL-mediated transport processes linked to downregulated DEGs in BPA lineage males and females. In contrast, the expression of genes encoding lipogenesis-related proteins was significantly elevated in the liver of BPA lineage females only. BPA lineage females exhibiting activation of myc, atf4, xbp1, stat4, and cancerous pathways, as well as inactivation of igf1, suggest their possible association with an advanced NAFLD phenotype. The present results suggest that gene networks involved in the progression of human NAFLD and the transgenerational NAFLD in medaka are conserved and that medaka can be an excellent animal model to understand the development and progression of liver disease and environmental influences in the liver.
Collapse
|
|
7
|
Lv M, Chen S, Shan M, Si Y, Huang C, Chen J, Gong L. Arctigenin induces activated HSCs quiescence via AMPK-PPARγ pathway to ameliorate liver fibrosis in mice. Eur J Pharmacol 2024; 974:176629. [PMID: 38679116 DOI: 10.1016/j.ejphar.2024.176629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/01/2024]
Abstract
Arctigenin (ATG), a traditional Chinese herbal medicine, is a natural lignan compound extracted from the seeds of burdock (Arctium lappa L, Asteraceae). As a natural product with multiple biological activities, the effect and mechanism of ATG against liver fibrosis are not fully elucidated yet. In current work, we first discovered that ATG could improve CCl4-induced liver injury reflected by lower plasma ALT and AST levels, liver coefficient and pathological scoring of ballooning. Furthermore, it also could reduce the positive areas of Masson, Sirius red and α-SMA staining, inhibit the expression of fibrosis-related genes (Col1a1, Col3a1, Acta2), and decrease the content of hydroxyproline, indicated ATG treatment had benefits in alleviating CCl4-induced liver fibrosis. In vitro, we observed that ATG can inhibit collagen production stimulated by TGF-β1 in LX2 cells. By analysis of the information obtained from SymMap and GeneCards databases and in vitro validation experiments, ATG was proven to be an indirect PPARγ agonist and its effect on collagen production was dependent on PPARγ. Subsequently, we confirmed that ATG activating AMPK was the contributor of its effect on PPARγ and collagen production. Finally, the transformation of activated hepatic stellate cells was determined after treated with ATG, in which ATG treatment could return activated LX2 cells to quiescence because of the elevated quiescent markers and lipid droplets. Our work has highlighted the potential of ATG in the treatment of liver fibrosis and clarified that ATG can activate AMPK/PPARγ pathway to restore the activated hepatic stellate cell to quiescence thereby improving liver fibrosis.
Collapse
Affiliation(s)
- Mengjia Lv
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Shiyi Chen
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Mengwen Shan
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Yuan Si
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China
| | - Chenggang Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
| | - Jing Chen
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
| | - Likun Gong
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
| |
Collapse
|
|
8
|
Chakraborty S, Anand S, Bhandari RK. Sex-specific expression of the human NAFLD-NASH transcriptional signatures in the liver of medaka with a history of ancestral bisphenol A exposure. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.19.594843. [PMID: 38826193 PMCID: PMC11142124 DOI: 10.1101/2024.05.19.594843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
The progression of fatty liver disease to non-alcoholic steatohepatitis (NASH) is a leading cause of death in humans. Lifestyles and environmental chemical exposures can increase the susceptibility of humans to NASH. In humans, the presence of bisphenol A (BPA) in urine is associated with fatty liver disease, but whether ancestral BPA exposure leads to the activation of human NAFLD-NASH-associated genes in the unexposed descendants is unclear. In this study, using medaka fish as an animal model for human NAFLD, we investigated the transcriptional signatures of human NAFLD-NASH and their associated roles in the pathogenesis of the liver of fish who were not directly exposed but their ancestors were exposed to BPA during embryonic and perinatal development three generations prior. Comparison of bulk RNA-Seq data of the liver in BPA lineage male and female medaka with publicly available human NAFLD-NASH patient data revealed transgenerational alterations in the transcriptional signature of human NAFLD-NASH in medaka liver. Twenty percent of differentially expressed genes (DEGs) were upregulated in both human NAFLD patients and medaka. Specifically in females, among the total shared DEGs in the liver of BPA lineage fish and NAFLD patient groups, 27.69% DEGs were downregulated and 20% DEGs were upregulated. Off all DEGs, 52.31% DEGs were found in ancestral BPA-lineage females, suggesting that NAFLD in females shared majority of human NAFLD gene networks. Pathway analysis revealed beta-oxidation, lipoprotein metabolism, and HDL/LDL-mediated transport processes linked to downregulated DEGs in BPA lineage males and females. In contrast, the expression of genes encoding lipogenesis-related proteins was significantly elevated in the liver of BPA lineage females only. BPA lineage females exhibiting activation of myc, atf4, xbp1, stat4, and cancerous pathways, as well as inactivation of igf1, suggest their possible association with an advanced NAFLD phenotype. The present results suggest that gene networks involved in the progression of human NAFLD and the transgenerational NAFLD in medaka are conserved and that medaka can be an excellent animal model to understand the development and progression of liver disease and environmental influences in the liver.
Collapse
Affiliation(s)
- Sourav Chakraborty
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, U.S.A
| | - Santosh Anand
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, U.S.A
| | - Ramji Kumar Bhandari
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, U.S.A
| |
Collapse
|
|
9
|
Boran T, Zengin OS, Seker Z, Akyildiz AG, Kara M, Oztas E, Özhan G. An evaluation of a hepatotoxicity risk induced by the microplastic polymethyl methacrylate (PMMA) using HepG2/THP-1 co-culture model. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2024; 31:28890-28904. [PMID: 38564126 PMCID: PMC11058773 DOI: 10.1007/s11356-024-33086-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
Inappropriate disposal of plastic wastes and their durability in nature cause uncontrolled accumulation of plastic in land/marine ecosystems, also causing destructive effects by bioaccumulating along the food chain. Microplastics may cause chronic inflammation in relation to their permanent structures, especially through oxidative stress and cytotoxic cellular damage, which could increase the risk of cancer development. The accumulation of microplastics in the liver is a major concern, and therefore, the identification of the mechanisms of their hepatotoxic effects is of great importance. Polymethyl methacrylate (PMMA) is a widely used thermoplastic. It has been determined that PMMA disrupts lipid metabolism in the liver in various aquatic organisms and causes reproductive and developmental toxicity. PMMA-induced hepatotoxic effects in humans have not yet been clarified. In our study, the toxic effects of PMMA (in the range of 3-10 μm) on the human liver were investigated using the HepG2/THP-1 macrophage co-culture model, which is a sensitive immune-mediated liver injury model. Cellular uptake of micro-sized PMMA in the cells was done by transmission electron microscopy. Determination of its effects on cell viability and inflammatory response, oxidative stress, along with gene and protein expression levels that play a role in the mechanism pathways underlying the effects were investigated. The results concluded that inflammation, oxidative stress, and disruptions in lipid metabolism should be the focus of attention as important underlying causes of PMMA-induced hepatotoxicity. Our study, which points out the potential adverse effects of microplastics on human health, supports the literature information on the subject.
Collapse
Affiliation(s)
- Tugce Boran
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University-Cerrahpaşa, Istanbul, Turkey
| | - Ozge Sultan Zengin
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
- Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Turkey
| | - Zehra Seker
- Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Turkey
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey
| | - Aysenur Gunaydin Akyildiz
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey
| | - Mehtap Kara
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Ezgi Oztas
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Gül Özhan
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.
| |
Collapse
|
|
10
|
Zhou C, Xia Q, Hamezah HS, Fan Z, Tong X, Han R. Efficacy of Forsythia suspensa (Thunb.) Vahl on mouse and rat models of inflammation-related diseases: a meta-analysis. Front Pharmacol 2024; 15:1288584. [PMID: 38500762 PMCID: PMC10946063 DOI: 10.3389/fphar.2024.1288584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 02/22/2024] [Indexed: 03/20/2024] Open
Abstract
Objective: To evaluate the efficacy of the fruits of the medicinal plant Forsythia suspensa (Thunb.) Vahl (FS), in treating inflammation-associated diseases through a meta-analysis of animal models, and also probe deeply into the signaling pathways underlying the progression of inflammation. Materials and methods: All data analyses were performed using Review Manager 5.3 and the results are presented as flow diagrams, risk-of-bias summaries, forest plots, and funnel plots. Summary estimates were calculated using a random- or fixed-effect model, depending on the value of I2. Results: Of the 710 records identified in the initial search, 11 were selected for the final meta-analysis. Each study extracted data from the model and treatment groups for analysis, and the results showed that FS alleviated the inflammatory cytokine levels in serum; oxidant indicator: reactive oxygen species; enzymes of liver function; endotoxin and regulatory cells in blood; and improved the antioxidant enzyme superoxide dismutase. Conclusion: FS effectively reversed the change in acute or chronic inflammation indicators in animal models, and the regulation of multiple channel proteins in inflammatory signaling pathways suggests that FS is a good potential drug for inflammatory disease drug therapy.
Collapse
Affiliation(s)
- Chenyu Zhou
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Quan Xia
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | | | - Zheng Fan
- Affiliated Taihe Hospital of Chinese Medicine, Anhui University of Chinese Medicine, Taihe, China
| | - Xiaohui Tong
- School of Life Sciences, Anhui University of Chinese Medicine, Hefei, China
- Functional Activity and Resource Utilization on Edible and Medicinal Fungi Joint Laboratory of Anhui Province, Jinzhai, China
| | - Rongchun Han
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Joint Research Center for Chinese Herbal Medicine of Anhui of IHM, Anhui University of Chinese Medicine, Hefei, China
| |
Collapse
|
|
11
|
Sinha RA. Targeting nuclear receptors for NASH/MASH: From bench to bedside. LIVER RESEARCH (BEIJING, CHINA) 2024; 8:34-45. [PMID: 38544909 PMCID: PMC7615772 DOI: 10.1016/j.livres.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/27/2023] [Accepted: 03/07/2024] [Indexed: 04/17/2024]
Abstract
The onset of metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). With no pharmacological treatment currently available for MASH/NASH, the race is on to develop drugs targeting multiple facets of hepatic metabolism, inflammation, and pro-fibrotic events, which are major drivers of MASH. Nuclear receptors (NRs) regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation. Ligands of NRs may include hormones, lipids, bile acids, and synthetic ligands, which upon binding to NRs regulate the transcriptional activities of target genes. NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH. This review aims to cover the current understanding of NRs, including nuclear hormone receptors, non-steroid hormone receptors, circadian NRs, and orphan NRs, which are currently undergoing clinical trials for MASH treatment, along with NRs that have shown promising results in preclinical studies.
Collapse
Affiliation(s)
- Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| |
Collapse
|
|
12
|
Ren X, Mao P, Li Z, Qian M, Deng X, Liu H, Wang L. TMT-based quantitative proteomics analysis of Sprague-Dawley rats liver reveals Triphenyltin induced liver damage and lipid metabolism disorders. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2024; 198:105739. [PMID: 38225084 DOI: 10.1016/j.pestbp.2023.105739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/27/2023] [Accepted: 12/06/2023] [Indexed: 01/17/2024]
Abstract
Triphenyltin (TPT) is a widely used pesticide that has a negative impact on biological health and production efficiency. In addition, TPT poses a threat to human health through the food chain and environmental pollution. However, the exact mechanism of TPT toxicity remains unclear. In this study, we investigated the hepatotoxicity of TPT and its effects on lipid metabolism using male SD rats as an animal model. Our results from HE and serum biochemical analysis suggested that TPT could damage liver structure and function, resulting in disruption of lipid metabolism. We therefore proceeded to analyze the proteomic response of rat liver tissue after 28 days of treatment with 2 mg/kg/d TPT. Our study demonstrates that TPT has a variety of effects on liver protein expression in rats. Through bioinformatic analysis, we observed significant changes in proteins related to fatty acid oxidation and synthesis due to TPT exposure. Furthermore, western blot and RT-qPCR experiments confirmed that TPT can affect lipid metabolism through the PPAR pathway. These findings suggest that TPT exposure can lead to liver damage, lipid accumulation and metabolic disorders.
Collapse
Affiliation(s)
- Xijuan Ren
- School of Public Health, Bengbu Medical College, Bengbu 233030, PR China
| | - Penghui Mao
- School of Public Health, Bengbu Medical College, Bengbu 233030, PR China
| | - Zhi Li
- School of Public Health, Bengbu Medical College, Bengbu 233030, PR China
| | - Mingqing Qian
- School of Public Health, Bengbu Medical College, Bengbu 233030, PR China
| | - Xinxin Deng
- School of Public Health, Bengbu Medical College, Bengbu 233030, PR China
| | - Hui Liu
- Bengbu Medical College Key Laboratory of Cancer Research and Clinical Laboratory Diagnosis, School of Laboratory Medicine, Bengbu Medical College, Bengbu 233030, PR China.
| | - Li Wang
- School of Public Health, Bengbu Medical College, Bengbu 233030, PR China.
| |
Collapse
|
|
13
|
Xiao J, Xiang H, Xiang H, Sun Z, Xu J, Ren H, Hu P, Peng M. GW9662 ameliorates nonalcoholic steatohepatitis by inhibiting the PPARγ/CD36 pathway and altering the gut microbiota. Eur J Pharmacol 2023; 960:176113. [PMID: 37838102 DOI: 10.1016/j.ejphar.2023.176113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 10/04/2023] [Accepted: 10/11/2023] [Indexed: 10/16/2023]
Abstract
BACKGROUND & AIMS Peroxisome proliferator-activated receptors (PPARs) are currently among the most focused-on therapeutic targets for non-alcoholic steatohepatitis (NASH), although no clinical transformation has been achieved to date. In this study, we aimed to evaluate the effects of GW9662 on choline-deficient, L-amino acid-defined high-fat diet (CDAA-HFD)-induced NASH mice and reveal the mechanism underlying this effect. METHODS GW9662 (1 mg/kg) was administered in CDAA-HFD mouse model of NASH. The effect of GW9662 on hepatic lipid metabolism was investigated using liver RNA-seq and HepG2 cells induced by oleic acid and palmitic acid. In addition, 16S rRNA gene sequencing was performed to analyze the effects of GW9662 on the composition and function of the fecal microbiota. RESULTS GW9662 improved the CDAA-HFD caused elevation in the levels of ALT, AST, hepatic free fatty acids and triglycerides. The liver pathological analysis indicated that GW9662 alleviated the hepatic steatosis and fibrosis. The NAFLD activity score and RNA-Seq revealed that GW9662 mainly regulated the fatty acids transport and lipid synthesis by inhibiting PPARγ, CD36, FABP1, FASN, and SCD1, and through the up-regulation of PPARα. Moreover, GW9662 reduced the epididymal fat weight. GW9662 reversed the gut microbiota disorder by increasing the abundance of the beneficial bacteria Dubosiella and Lactobacillus and decreasing the abundance of harmful bacteria Lachnospiraceae_NK4A136_group, Helicobacteraceae, Desulfovibriaceae, and Rickenaceae. CONCLUSIONS GW9662 ameliorated lipid metabolism by inhibiting the PPARγ/CD36 pathway and altering the composition of the gut microbiota in NASH mice. Therefore, the PPARγ antagonist GW9662 deserves more attention as a potential therapeutic agent for NASH.
Collapse
Affiliation(s)
- Jing Xiao
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Huanyu Xiang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hongyan Xiang
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zilin Sun
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jing Xu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Mingli Peng
- Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| |
Collapse
|
|
14
|
Hong T, Xiong X, Chen Y, Wang Q, Fu X, Meng Q, Lu Y, Li X. Parathyroid hormone receptor-1 signaling aggravates hepatic fibrosis through upregulating cAMP response element-binding protein-like 2. Hepatology 2023; 78:1763-1776. [PMID: 36939197 DOI: 10.1097/hep.0000000000000333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 01/23/2023] [Indexed: 03/21/2023]
Abstract
BACKGROUND AND AIMS Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of HSCs and hepatic fibrosis was examined. APPROACH AND RESULTS PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl 4 )-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl 4 , MCD, or western diet, plus low-dose CCl 4 -induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl 4 -treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of TGFβ in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl 4 -treated mice. CONCLUSIONS In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs through Crebl2/SMAD3/TGFβ regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.
Collapse
Affiliation(s)
- Ting Hong
- Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xuelian Xiong
- Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yaqiong Chen
- Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qiuyu Wang
- Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao Fu
- Department of General Surgery, Institute of Translational Medicine, Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qingnan Meng
- Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yan Lu
- Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoying Li
- Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| |
Collapse
|
|
15
|
Liu R, Scimeca M, Sun Q, Melino G, Mauriello A, Shao C, Shi Y, Piacentini M, Tisone G, Agostini M. Harnessing metabolism of hepatic macrophages to aid liver regeneration. Cell Death Dis 2023; 14:574. [PMID: 37644019 PMCID: PMC10465526 DOI: 10.1038/s41419-023-06066-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/31/2023] [Accepted: 08/14/2023] [Indexed: 08/31/2023]
Abstract
Liver regeneration is a dynamic and regulated process that involves inflammation, granulation, and tissue remodeling. Hepatic macrophages, abundantly distributed in the liver, are essential components that actively participate in each step to orchestrate liver regeneration. In the homeostatic liver, resident macrophages (Kupffer cells) acquire a tolerogenic phenotype and contribute to immunological tolerance. Following toxicity-induced damage or physical resection, Kupffer cells as well as monocyte-derived macrophages can be activated and promote an inflammatory process that supports the survival and activation of hepatic myofibroblasts and thus promotes scar tissue formation. Subsequently, these macrophages, in turn, exhibit the anti-inflammatory effects critical to extracellular matrix remodeling during the resolution stage. However, continuous damage-induced chronic inflammation generally leads to hepatic macrophage dysfunction, which exacerbates hepatocellular injury and triggers further liver fibrosis and even cirrhosis. Emerging macrophage-targeting strategies have shown efficacy in both preclinical and clinical studies. Increasing evidence indicates that metabolic rewiring provides substrates for epigenetic modification, which endows monocytes/macrophages with prolonged "innate immune memory". Therefore, it is reasonable to conceive novel therapeutic strategies for metabolically reprogramming macrophages and thus mediate a homeostatic or reparative process for hepatic inflammation management and liver regeneration.
Collapse
Affiliation(s)
- Rui Liu
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Manuel Scimeca
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Qiang Sun
- Institute of Biotechnology, Academy of Military Medical Science; Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, 100071, Beijing, China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Alessandro Mauriello
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Changshun Shao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College of Soochow University, 215123, Suzhou, Jiangsu, China
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, 215123, Suzhou, China.
| | - Mauro Piacentini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Giuseppe Tisone
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Massimiliano Agostini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| |
Collapse
|
|
16
|
Aibara D, Sakaguchi A, Matsusue K. Transcriptional regulation of adipogenin expression in liver steatosis by hepatic peroxisome proliferator-activated receptor gamma. Genes Cells 2023; 28:585-594. [PMID: 37249025 DOI: 10.1111/gtc.13052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/08/2023] [Accepted: 05/10/2023] [Indexed: 05/31/2023]
Abstract
The nuclear receptors peroxisome proliferator-activated receptor gamma (PPARγ) and adipogenin (ADIG) play vital roles in lipid metabolism. However, the interaction between PPARγ and ADIG during liver steatosis remains unclear. In this study, we aimed to investigate the role of PPARγ in the transcriptional regulation of hepatic ADIG expression. Adig was found to be highly expressed in various fatty liver mouse models. Although hepatic Adig was expressed at high levels in the fatty liver of type 2 diabetic ob/ob mice and was upregulated by PPARγ agonist treatment, it was expressed at significantly low levels in liver-specific Pparg-knockout mice. Moreover, hepatic Adig expression was observed in other mouse models of liver steatosis, such as the leptin receptor mutant db/db and alcohol-fed mice. Adig was also highly expressed in the white and brown adipose tissues, skeletal muscles, and heart of ob/ob mice. Reporter and electromobility shift assays showed that PPARγ positively regulates Adig transcriptional activity by directly binding to a functional PPARγ-responsive element in the promoter region. Our results indicate that Adig is a novel target gene of hepatic PPARγ in liver steatosis.
Collapse
Affiliation(s)
- Daisuke Aibara
- Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka, Japan
| | - Ai Sakaguchi
- Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka, Japan
| | - Kimihiko Matsusue
- Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka, Japan
| |
Collapse
|
|
17
|
Song Q, Wang J, Griffiths A, Lee SM, Iyamu ID, Huang R, Cordoba-Chacon J, Song Z. Nicotinamide N-methyltransferase upregulation contributes to palmitate-elicited peroxisome proliferator-activated receptor transactivation in hepatocytes. Am J Physiol Cell Physiol 2023; 325:C29-C41. [PMID: 37212549 PMCID: PMC10259858 DOI: 10.1152/ajpcell.00010.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/15/2023] [Accepted: 05/16/2023] [Indexed: 05/23/2023]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) plays a pivotal role in regulating lipid metabolism and hepatic PPARγ transactivation contributes to fatty liver development. Fatty acids (FAs) are well-known endogenous ligands for PPARγ. Palmitate, a 16-C saturated FA (SFA) and the most abundant SFA in human circulation, is a strong inducer of hepatic lipotoxicity, a central pathogenic factor for various fatty liver diseases. In this study, using both alpha mouse liver 12 (AML12) and primary mouse hepatocytes, we investigated the effects of palmitate on hepatic PPARγ transactivation and underlying mechanisms, as well as the role of PPARγ transactivation in palmitate-induced hepatic lipotoxicity, all of which remain ambiguous currently. Our data revealed that palmitate exposure was concomitant with both PPARγ transactivation and upregulation of nicotinamide N-methyltransferase (NNMT), a methyltransferase catalyzing the degradation of nicotinamide, the predominant precursor for cellular NAD+ biosynthesis. Importantly, we discovered that PPARγ transactivation by palmitate was blunted by NNMT inhibition, suggesting that NNMT upregulation plays a mechanistic role in PPARγ transactivation. Further investigations uncovered that palmitate exposure is associated with intracellular NAD+ decline and NAD+ replenishment with NAD+-enhancing agents, nicotinamide and nicotinamide riboside, obstructed palmitate-induced PPARγ transactivation, implying that cellular NAD+ decline resulted from NNMT upregulation represents a potential mechanism behind palmitate-elicited PPARγ transactivation. At last, our data showed that the PPARγ transactivation marginally ameliorated palmitate-induced intracellular triacylglycerol accumulation and cell death. Collectively, our data provided the first-line evidence supporting that NNMT upregulation plays a mechanistic role in palmitate-elicited PPARγ transactivation, potentially through reducing cellular NAD+ contents.NEW & NOTEWORTHY Hepatic PPARγ transactivation contributes to fatty liver development. Saturated fatty acids (SFAs) induce hepatic lipotoxicity. Here, we investigated whether and how palmitate, the most abundant SFA in the human blood, affects PPARγ transactivation in hepatocytes. We reported for the first time that upregulation of nicotinamide N-methyltransferase (NNMT), a methyltransferase catalyzing the degradation of nicotinamide, the predominant precursor for cellular NAD+ biosynthesis, plays a mechanistic role in regulating palmitate-elicited PPARγ transactivation through reducing intracellular NAD+ contents.
Collapse
Affiliation(s)
- Qing Song
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Jun Wang
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Alexandra Griffiths
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Samuel Man Lee
- Division of Endocrinology/Diabetes & Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Iredia D Iyamu
- Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, United States
| | - Rong Huang
- Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, United States
| | - Jose Cordoba-Chacon
- Division of Endocrinology/Diabetes & Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Zhenyuan Song
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States
| |
Collapse
|
|
18
|
Basha A, May SC, Anderson RM, Samala N, Mirmira RG. Non-Alcoholic Fatty Liver Disease: Translating Disease Mechanisms into Therapeutics Using Animal Models. Int J Mol Sci 2023; 24:9996. [PMID: 37373143 PMCID: PMC10298283 DOI: 10.3390/ijms24129996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a range of pathologies arising from fat accumulation in the liver in the absence of excess alcohol use or other causes of liver disease. Its complications include cirrhosis and liver failure, hepatocellular carcinoma, and eventual death. NAFLD is the most common cause of liver disease globally and is estimated to affect nearly one-third of individuals in the United States. Despite knowledge that the incidence and prevalence of NAFLD are increasing, the pathophysiology of the disease and its progression to cirrhosis remain insufficiently understood. The molecular pathogenesis of NAFLD involves insulin resistance, inflammation, oxidative stress, and endoplasmic reticulum stress. Better insight into these molecular pathways would allow for therapies that target specific stages of NAFLD. Preclinical animal models have aided in defining these mechanisms and have served as platforms for screening and testing of potential therapeutic approaches. In this review, we will discuss the cellular and molecular mechanisms thought to contribute to NAFLD, with a focus on the role of animal models in elucidating these mechanisms and in developing therapies.
Collapse
Affiliation(s)
- Amina Basha
- Kovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Sarah C. May
- Kovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Ryan M. Anderson
- Kovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Niharika Samala
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Raghavendra G. Mirmira
- Kovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| |
Collapse
|
|
19
|
Yum YJ, Yoo J, Bang K, Jun JE, Jeong IK, Ahn KJ, Chung HY, Hwang YC. Peroxisome proliferator-activated receptor γ activation ameliorates liver fibrosis-differential action of transcription factor EB and autophagy on hepatocytes and stellate cells. Hepatol Commun 2023; 7:e0154. [PMID: 37204406 PMCID: PMC10538880 DOI: 10.1097/hc9.0000000000000154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/07/2023] [Indexed: 05/20/2023] Open
Abstract
BACKGROUND Peroxisome proliferator-activated receptor γ (PPARγ) activation suppresses HSC activation and liver fibrosis. Moreover, autophagy is implicated in hepatic lipid metabolism. Here, we determined whether PPARγ activation ameliorates HSC activation by downregulating transcription factor EB (TFEB)-mediated autophagy. METHODS AND RESULTS Atg7 or Tfeb knockdown in human HSC line LX-2 cells downregulated the expression of fibrogenic markers including α smooth muscle actin, glial fibrillary acidic protein, and collagen type 1. Conversely, Atg7 or Tfeb overexpression upregulated fibrogenic marker expression. Rosiglitazone (RGZ)-mediated PPARγ activation and/or overexpression in LX-2 cells and primary HSCs decreased autophagy, as indicated by LC3B conversion, total and nuclear-TFEB contents, mRFP-LC3 and BODIPY 493/503 colocalization, and GFP-LC3 and LysoTracker colocalization. RGZ treatment decreased liver fat content, liver enzyme levels, and fibrogenic marker expression in high-fat high-cholesterol diet-fed mice. Electron microscopy showed that RGZ treatment restored the high-fat high-cholesterol diet-mediated lipid droplet decrease and autophagic vesicle induction in primary HSCs and liver tissues. However, TFEB overexpression in LX-2 cells offset the aforementioned effects of RGZ on autophagic flux, lipid droplets, and fibrogenic marker expression. CONCLUSIONS Activation of PPARγ with RGZ ameliorated liver fibrosis and downregulation of TFEB and autophagy in HSCs may be important for the antifibrotic effects of PPARγ activation.
Collapse
|
|
20
|
Chen H, Tan H, Wan J, Zeng Y, Wang J, Wang H, Lu X. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2023; 245:108391. [PMID: 36963510 DOI: 10.1016/j.pharmthera.2023.108391] [Citation(s) in RCA: 90] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/20/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), currently the leading cause of global chronic liver disease, has emerged as a major public health problem, more efficient therapeutics of which are thus urgently needed. Peroxisome proliferator-activated receptor γ (PPAR-γ), ligand-activated transcription factors of the nuclear hormone receptor superfamily, is considered a crucial metabolic regulator of hepatic lipid metabolism and inflammation. The role of PPAR-γ in the pathogenesis of NAFLD is gradually being recognized. Here, we outline the involvement of PPAR-γ in the pathogenesis of NAFLD through adipogenesis, insulin resistance, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In addition, the evidence for PPAR-γ- targeted therapy for NAFLD are summarized. Altogether, PPAR-γ is a promising therapeutic target for NAFLD, and the development of drugs that can balance the beneficial and undesirable effects of PPAR-γ will bring new light to NAFLD patients.
Collapse
Affiliation(s)
- Hao Chen
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Juan Wan
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine / West China School of Nursing, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jincheng Wang
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haichuan Wang
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| |
Collapse
|
|
21
|
Guha Ray A, Odum OP, Wiseman D, Weinstock A. The diverse roles of macrophages in metabolic inflammation and its resolution. Front Cell Dev Biol 2023; 11:1147434. [PMID: 36994095 PMCID: PMC10041730 DOI: 10.3389/fcell.2023.1147434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023] Open
Abstract
Macrophages are one of the most functionally diverse immune cells, indispensable to maintain tissue integrity and metabolic health. Macrophages perform a myriad of functions ranging from promoting inflammation, through inflammation resolution to restoring and maintaining tissue homeostasis. Metabolic diseases encompass a growing list of diseases which develop from a mix of genetics and environmental cues leading to metabolic dysregulation and subsequent inflammation. In this review, we summarize the contributions of macrophages to four metabolic conditions-insulin resistance and adipose tissue inflammation, atherosclerosis, non-alcoholic fatty liver disease and neurodegeneration. The role of macrophages is complex, yet they hold great promise as potential therapies to address these growing health concerns.
Collapse
Affiliation(s)
| | | | | | - Ada Weinstock
- Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, United States
| |
Collapse
|
|
22
|
Duran-Güell M, Garrabou G, Flores-Costa R, Casulleras M, López-Vicario C, Zhang IW, Cantó-Santos J, Contreras BJ, Sánchez-Rodríguez MB, Romero-Grimaldo B, Horrillo R, Costa M, Arroyo V, Clària J. Essential role for albumin in preserving liver cells from TNFα-induced mitochondrial injury. FASEB J 2023; 37:e22817. [PMID: 36809676 DOI: 10.1096/fj.202201526r] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/13/2023] [Accepted: 01/30/2023] [Indexed: 02/23/2023]
Abstract
Cytokine-induced inflammation and mitochondrial oxidative stress are key drivers of liver tissue injury. Here, we describe experiments modeling hepatic inflammatory conditions in which plasma leakage leads to large amounts of albumin to reach the interstitium and parenchymal surfaces to explore whether this protein plays a role in preserving hepatocyte mitochondria against the damaging actions of the cytotoxic cytokine tumor necrosis factor alpha (TNFα). Hepatocytes and precision-cut liver slices were cultured in the absence or presence of albumin in the cell media and then exposed to mitochondrial injury with the cytokine TNFα. The homeostatic role of albumin was also investigated in a mouse model of TNFα-mediated liver injury induced by lipopolysaccharide and D-galactosamine (LPS/D-gal). Mitochondrial ultrastructure, oxygen consumption, ATP and reactive oxygen species (ROS) generation, fatty acid β-oxidation (FAO), and metabolic fluxes were assessed by transmission electron microscopy (TEM), high-resolution respirometry, luminescence-fluorimetric-colorimetric assays and NADH/FADH2 production from various substrates, respectively. TEM analysis revealed that in the absence of albumin, hepatocytes were more susceptible to the damaging actions of TNFα and showed more round-shaped mitochondria with less intact cristae than hepatocytes cultured with albumin. In the presence of albumin in the cell media, hepatocytes also showed reduced mitochondrial ROS generation and FAO. The mitochondria protective actions of albumin against TNFα damage were associated with the restoration of a breakpoint between isocitrate and α-ketoglutarate in the tricarboxylic acid cycle and the upregulation of the antioxidant activating transcription factor 3 (ATF3). The involvement of ATF3 and its downstream targets was confirmed in vivo in mice with LPS/D-gal-induced liver injury, which showed increased hepatic glutathione levels, indicating a reduction in oxidative stress after albumin administration. These findings reveal that the albumin molecule is required for the effective protection of liver cells from mitochondrial oxidative stress induced by TNFα. These findings emphasize the importance of maintaining the albumin levels in the interstitial fluid within the normal range to protect the tissues against inflammatory injury in patients with recurrent hypoalbuminemia.
Collapse
Affiliation(s)
- Marta Duran-Güell
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,Grifols Chair, European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Glòria Garrabou
- Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences, Internal Medicine Department, University of Barcelona, Hospital Clínic, Barcelona, Spain.,CIBERer, Barcelona, Spain
| | - Roger Flores-Costa
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,Grifols Chair, European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Mireia Casulleras
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,Grifols Chair, European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Cristina López-Vicario
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,Grifols Chair, European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain.,CIBERehd, Barcelona, Spain
| | - Ingrid W Zhang
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,Grifols Chair, European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Judith Cantó-Santos
- Muscle Research and Mitochondrial Function Laboratory, Cellex-IDIBAPS, Faculty of Medicine and Health Sciences, Internal Medicine Department, University of Barcelona, Hospital Clínic, Barcelona, Spain.,CIBERer, Barcelona, Spain
| | - Bryan J Contreras
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain
| | | | - Berta Romero-Grimaldo
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain
| | | | | | - Vicente Arroyo
- Grifols Chair, European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Joan Clària
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, Barcelona, Spain.,Grifols Chair, European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain.,CIBERehd, Barcelona, Spain.,Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
23
|
Recinella L, De Filippis B, Libero ML, Ammazzalorso A, Chiavaroli A, Orlando G, Ferrante C, Giampietro L, Veschi S, Cama A, Mannino F, Gasparo I, Bitto A, Amoroso R, Brunetti L, Leone S. Anti-Inflammatory, Antioxidant, and WAT/BAT-Conversion Stimulation Induced by Novel PPAR Ligands: Results from Ex Vivo and In Vitro Studies. Pharmaceuticals (Basel) 2023; 16:346. [PMID: 36986448 PMCID: PMC10056895 DOI: 10.3390/ph16030346] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/21/2023] [Accepted: 02/21/2023] [Indexed: 03/02/2023] Open
Abstract
Activation of peroxisome proliferator-activated receptors (PPARs) not only regulates multiple metabolic pathways, but mediates various biological effects related to inflammation and oxidative stress. We investigated the effects of four new PPAR ligands containing a fibrate scaffold-the PPAR agonists (1a (αEC50 1.0 μM) and 1b (γEC50 0.012 μM)) and antagonists (2a (αIC50 6.5 μM) and 2b (αIC50 0.98 μM, with a weak antagonist activity on γ isoform))-on proinflammatory and oxidative stress biomarkers. The PPAR ligands 1a-b and 2a-b (0.1-10 μM) were tested on isolated liver specimens treated with lipopolysaccharide (LPS), and the levels of lactate dehydrogenase (LDH), prostaglandin (PG) E2, and 8-iso-PGF2α were measured. The effects of these compounds on the gene expression of the adipose tissue markers of browning, PPARα, and PPARγ, in white adipocytes, were evaluated as well. We found a significant reduction in LPS-induced LDH, PGE2, and 8-iso-PGF2α levels after 1a treatment. On the other hand, 1b decreased LPS-induced LDH activity. Compared to the control, 1a stimulated uncoupling protein 1 (UCP1), PR-(PRD1-BF1-RIZ1 homologous) domain containing 16 (PRDM16), deiodinase type II (DIO2), and PPARα and PPARγ gene expression, in 3T3-L1 cells. Similarly, 1b increased UCP1, DIO2, and PPARγ gene expression. 2a-b caused a reduction in the gene expression of UCP1, PRDM16, and DIO2 when tested at 10 μM. In addition, 2a-b significantly decreased PPARα gene expression. A significant reduction in PPARγ gene expression was also found after 2b treatment. The novel PPARα agonist 1a might be a promising lead compound and represents a valuable pharmacological tool for further assessment. The PPARγ agonist 1b could play a minor role in the regulation of inflammatory pathways.
Collapse
Affiliation(s)
- Lucia Recinella
- Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy
| | | | | | | | | | - Giustino Orlando
- Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy
| | - Claudio Ferrante
- Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy
| | | | - Serena Veschi
- Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy
| | - Alessandro Cama
- Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy
| | - Federica Mannino
- Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
| | - Irene Gasparo
- Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
| | - Alessandra Bitto
- Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
| | - Rosa Amoroso
- Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy
| | - Luigi Brunetti
- Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy
| | - Sheila Leone
- Department of Pharmacy, G. d’Annunzio University, 66100 Chieti, Italy
| |
Collapse
|
|
24
|
Lee E, Korf H, Vidal-Puig A. An adipocentric perspective on the development and progression of non-alcoholic fatty liver disease. J Hepatol 2023; 78:1048-1062. [PMID: 36740049 DOI: 10.1016/j.jhep.2023.01.024] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/20/2022] [Accepted: 01/19/2023] [Indexed: 02/07/2023]
Abstract
Alongside the liver, white adipose tissue (WAT) is critical in regulating systemic energy homeostasis. Although each organ has its specialised functions, they must work coordinately to regulate whole-body metabolism. Adipose tissues and the liver are relatively resilient and can adapt to an energy surplus by facilitating triglyceride (TG) storage up to a certain threshold level without significant metabolic disturbances. However, lipid storage in WAT beyond a "personalised" adiposity threshold becomes dysfunctional, leading to metabolic inflexibility, progressive inflammation, and aberrant adipokine secretion. Moreover, the failure of adipose tissue to store and mobilise lipids results in systemic knock-on lipid overload, particularly in the liver. Factors contributing to hepatic lipid overload include lipids released from WAT, dietary fat intake, and enhanced de novo lipogenesis. In contrast, extrahepatic mechanisms counteracting toxic hepatic lipid overload entail coordinated compensation through oxidation of surplus fatty acids in brown adipose tissue and storage of fatty acids as TGs in WAT. Failure of these integrated homeostatic mechanisms leads to quantitative increases and qualitative alterations to the lipidome of the liver. Initially, hepatocytes preferentially accumulate TG species leading to a relatively "benign" non-alcoholic fatty liver. However, with time, inflammatory responses ensue, progressing into more severe conditions such as non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma, in some individuals (often without an early prognostic clue). Herein, we highlight the pathogenic importance of obesity-induced "adipose tissue failure", resulting in decreased adipose tissue functionality (i.e. fat storage capacity and metabolic flexibility), in the development and progression of NAFL/NASH.
Collapse
Affiliation(s)
- Eunyoung Lee
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Hannelie Korf
- Laboratory of Hepatology, CHROMETA Department, KU Leuven, Leuven, Belgium.
| | - Antonio Vidal-Puig
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Centro de Innvestigacion Principe Felipe, Valencia, Spain; Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, China.
| |
Collapse
|
|
25
|
Ali Mondal S, Sathiaseelan R, Mann SN, Kamal M, Luo W, Saccon TD, Isola JVV, Peelor FF, Li T, Freeman WM, Miller BF, Stout MB. 17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice. Am J Physiol Endocrinol Metab 2023; 324:E120-E134. [PMID: 36516471 PMCID: PMC9902223 DOI: 10.1152/ajpendo.00256.2022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/15/2022]
Abstract
Estrogen signaling is protective against chronic liver diseases, although men and a subset of women are contraindicated for chronic treatment with 17β-estradiol (17β-E2) or combination hormone replacement therapies. We sought to determine if 17α-estradiol (17α-E2), a naturally occurring diastereomer of 17β-E2, could attenuate liver fibrosis. We evaluated the effects of 17α-E2 treatment on collagen synthesis and degradation rates using tracer-based labeling approaches in male mice subjected to carbon tetrachloride (CCl4)-induced liver fibrosis. We also assessed the effects of 17α-E2 on markers of hepatic stellate cell (HSC) activation, collagen cross-linking, collagen degradation, and liver macrophage content and polarity. We found that 17α-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor β1 (TGF-β1) and lysyl oxidase-like 2 (LOXL2) protein content in liver. These improvements were associated with increased matrix metalloproteinase 2 (MMP2) activity and suppressed stearoyl-coenzyme A desaturase 1 (SCD1) protein levels, the latter of which has been linked to the resolution of liver fibrosis. We also found that 17α-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-β1 signaling, and reduced proinflammatory macrophage activation and cytokines expression in the liver. We conclude that 17α-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mechanisms. Future studies will be needed to determine if 17α-E2 acts directly in hepatocytes, HSCs, and/or immune cells to elicit these benefits.
Collapse
Affiliation(s)
- Samim Ali Mondal
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Roshini Sathiaseelan
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Shivani N Mann
- Department of Neuroscience, University of Arizona, Tucson, Arizona
| | - Maria Kamal
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Wenyi Luo
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Tatiana D Saccon
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - José V V Isola
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Frederick F Peelor
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Tiangang Li
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Willard M Freeman
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma
| | - Benjamin F Miller
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma
| | - Michael B Stout
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
- Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma
| |
Collapse
|
|
26
|
Lee SM, Muratalla J, Karimi S, Diaz-Ruiz A, Frutos MD, Guzman G, Ramos-Molina B, Cordoba-Chacon J. Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice. Cell Mol Life Sci 2023; 80:39. [PMID: 36629912 PMCID: PMC10082675 DOI: 10.1007/s00018-022-04629-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/14/2022] [Accepted: 11/10/2022] [Indexed: 01/12/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis.
Collapse
Affiliation(s)
- Samuel M Lee
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA
| | - Jose Muratalla
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA
| | - Saman Karimi
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Maria Dolores Frutos
- Department of General and Digestive System Surgery, Virgen de La Arrixaca University Hospital, Murcia, Spain
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Bruno Ramos-Molina
- Obesity and Metabolism Group, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Jose Cordoba-Chacon
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA.
| |
Collapse
|
|
27
|
Ni XX, Ji PX, Chen YX, Li XY, Sheng L, Lian M, Guo CJ, Hua J. Regulation of the macrophage-hepatic stellate cell interaction by targeting macrophage peroxisome proliferator-activated receptor gamma to prevent non-alcoholic steatohepatitis progression in mice. Liver Int 2022; 42:2696-2712. [PMID: 36165186 DOI: 10.1111/liv.15441] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Macrophages display remarkable plasticity and can interact with surrounding cells to affect hepatic immunity and tissue remodelling during the progression of liver diseases. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a critical role in macrophage maturation, polarization and metabolism. In this study, we investigated the role of PPARγ in macrophage-hepatic stellate cell (HSC) interaction during non-alcoholic steatohepatitis (NASH) development. METHODS Wild-type, Ppargfl/fl and PpargΔLyz2 mice were fed a methionine- and choline-deficient (MCD) diet to induce NASH. Depletion of macrophages was performed using an injection of gadolinium chloride intraperitoneally. PPARγ-overexpressing or PPARγ-knockout macrophages were stimulated with saturated fatty acid (SFA) and cocultured with HSCs in a conditioned medium or the transwell coculture system. RESULTS Depletion of macrophages inhibited HSC activation and ameliorated NASH progression in MCD diet-fed mice. Coculturing HSCs with macrophages or culturing HSCs in a macrophage-conditioned medium-facilitated HSC activation, and this effect was magnified when macrophages were metabolically activated by SFA. Moreover, the absence of PPARγ in macrophages enhanced metabolic activation, promoting the migration and activation of HSCs through IL-1β and CCL2. In contrast, overexpression of PPARγ in macrophages obtained the opposite effects. In vivo, macrophage-specific PPARγ knockout affected the phenotype of hepatic macrophages and HSCs, involving the MAPK and NLRP3/caspase-1/IL-1β signalling pathways. Infiltrating hepatic monocyte-derived macrophages became the predominant macrophages in NASH liver, especially in PpargΔLyz2 mice, paralleling with aggravated inflammation and fibrosis. CONCLUSIONS Regulating macrophage PPARγ affected the metabolic activation of macrophages and their interaction with HSCs. Macrophage-specific PPARγ may be an attractive therapeutic target for protecting against NASH-associated inflammation and fibrosis.
Collapse
Affiliation(s)
- Xi Xi Ni
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Pei Xuan Ji
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Xin Chen
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao Yun Li
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Sheng
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Min Lian
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Can Jie Guo
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Hua
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
28
|
Zhang H, Zhou P, Xing W, Chen L, Zhou Y, Yang H, Fu K, Liu Z. GLIS2 Prevents Hepatic Fibrosis by Competitively Binding HDAC3 to Inhibit Hepatic Stellate Cell Activation. Cell Mol Gastroenterol Hepatol 2022; 15:355-372. [PMID: 36397300 PMCID: PMC9792572 DOI: 10.1016/j.jcmgh.2022.10.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/20/2022] [Accepted: 10/20/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND The role of GLIS2 in fibrotic diseases is controversial. GLIS2 deficiency has been reported to contribute to renal fibrosis in mice and has also been reported to prevent high lipid-induced mice hepatic fibrosis. METHODS Hepatic fibrosis in mice was induced by CCl4. Hematoxylin and eosin, Masson, Sirius red, and enzyme-linked immunosorbent assay were used to detect and evaluate the stage of hepatic fibrosis in humans or mice. A study model of tetracycline-responsive GLIS2 knockout hepatic stellate cells (HSCs) was constructed and named GLIS2-SG-Dox. By adding transforming growth factor β1 to stimulate the transdifferentiation of HSCs, the activation status of HSCs was comprehensively evaluated from the aspects of cell proliferation, migration, and the amount of lipid droplets. In mechanistic studies, dual-luciferase, coimmunoprecipitation, yeast two-hybrid system, chromatin immunoprecipitation, and DNA pulldown were performed to investigate or to prove the molecular mechanism that GLIS2 was involved in regulating liver fibrosis. Throughout the study, real-time fluorescence polymerase chain reaction (quantitative reverse-transcription polymerase chain reaction) was used to detect the relative abundance of messenger RNA expression of each target gene, Western blot was used to detect the relative abundance of protein, and immunohistochemistry or immunofluorescence was used to observe the subcellular localization of the target protein. RESULTS The expression of GLIS2 was significantly decreased in human liver fibrosis tissues and CCL4-induced mouse liver fibrosis tissues, especially in HSCs. In the GLIS2-SG-Dox cells, the peroxisome proliferator-activated receptor γ (PPAR-γ) pathway was inactive and cells underwent myofibroblastic transdifferentiation transformation. Overexpression of GLIS2 can increase the acetylation level of PPAR-γ and alleviate CCL4-induced liver fibrosis in mice. Mechanically, relatively abundant GLIS2 and histone deacetylase 3 (HDAC3) form chelates to avoid the deacetylation of PPAR-γ, so as to maintain the activation level of PPAR-γ signaling pathway in HSCs cells. In this process, HDAC3 acts as a medium for GLIS2 to influence PPAR-γ signaling. Nonetheless, when GLIS2 is absent, HDAC3 deacetylates PPAR-γ, activates HSCs, and leads to liver fibrosis. CONCLUSIONS GLIS2 deficiency promotes myofibroblastic transdifferentiation and activation of HSCs. Mechanically, GLIS2 regulates the acetylation of PPAR-γ by competitively binding to HDAC3 in HSCs.
Collapse
Affiliation(s)
- Haoye Zhang
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Pengcheng Zhou
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China; Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Wu Xing
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Limin Chen
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Yangmei Zhou
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Hui Yang
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Kangkang Fu
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Zhenguo Liu
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China; Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
| |
Collapse
|
|
29
|
Zhao D, Xue C, Yang Y, Li J, Wang X, Chen Y, Zhang S, Chen Y, Duan Y, Yang X, Han J. Lack of Nogo-B expression ameliorates PPARγ deficiency-aggravated liver fibrosis by regulating TLR4-NF-κB-TNF-α axis and macrophage polarization. Biomed Pharmacother 2022; 153:113444. [DOI: 10.1016/j.biopha.2022.113444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/09/2022] [Accepted: 07/18/2022] [Indexed: 11/02/2022] Open
|
|
30
|
Wu X, Gu X, Xue M, Ge C, Liang X. Proteomic analysis of hepatic fibrosis induced by a high starch diet in largemouth bass (Micropterus salmoides). COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2022; 43:101007. [PMID: 35714397 DOI: 10.1016/j.cbd.2022.101007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/26/2022] [Accepted: 06/05/2022] [Indexed: 06/15/2023]
Abstract
Largemouth bass is sensitive to the dietary starch level and excess starch can induce metabolic liver diseases (MLD). Hepatic fibrosis is a typical pathological phenotype of MLD in largemouth bass, but the molecular basis underlying is largely unclear. This study fed fish with a low or high starch diet for 4 weeks. Liver tissues with or without fibrotic symptoms were recognized through histopathological and molecular markers analysis of hepatic fibrosis, following TMT Quantitative proteomics and conducted Parallel Reaction Monitoring (PRM) analyses. 2455 differentially expressed proteins with 1618 up-regulated and 837 down-regulated were identified in this study. In GO terms, up-regulated proteins were correlated with cytoskeleton organization, supramolecular fiber, cytoskeleton protein binding, and actin-binding, while down-regulated proteins were involved in mainly metabolism-related processes, and molecular binding activity. Down-regulated proteins were enriched in 63 KEGG pathways and concentrated in metabolism-related pathways, especially glucose, lipid, and amino acid metabolism. 70 KEGG pathways of up-regulated proteins mainly included immunity and inflammation-related pathways. The expression trends of 11 differentially expressed proteins were consistent with proteome results by PRM analysis. In conclusion, the development of hepatic fibrosis induced by high starch may be related to multi-signaling pathways, metabolism processes, and targets, which provides important data for further study on revealing the molecular mechanism of hepatic fibrosis.
Collapse
Affiliation(s)
- Xiaoliang Wu
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Xu Gu
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Min Xue
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Chunyu Ge
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Xiaofang Liang
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
| |
Collapse
|
|
31
|
Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
Collapse
Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
| |
Collapse
|
|
32
|
Li XY, Ji PX, Ni XX, Chen YX, Sheng L, Lian M, Guo CJ, Hua J. Regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease. World J Hepatol 2022; 14:1365-1381. [PMID: 36158922 PMCID: PMC9376780 DOI: 10.4254/wjh.v14.i7.1365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/09/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Various studies have shown that PPAR-γ exerts potent anti-inflammatory and immunomodulatory properties. However, little is known about the regulation of PPAR-γ activity in modulating cell crosstalk in NAFLD.
AIM To investigate whether the regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation.
METHODS Primary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocyte-specific PPAR-γ knockout mice and incubated with free fatty acids (FFAs). Macrophages were incubated with conditioned medium (CM) from lipid-laden hepatocytes with or without a PPAR-γ agonist. Wild-type C57BL/6J mice were fed a high-fat (HF) diet and administered rosiglitazone.
RESULTS Primary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs. CM from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway. A PPAR-γ agonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization. Hepatocyte-specific PPAR-γ deficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes, which further promoted M1 macrophage polarization. Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.
CONCLUSION Upregulation of PPAR-γ activity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1β pathway.
Collapse
Affiliation(s)
- Xiao-Yun Li
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Pei-Xuan Ji
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Xi-Xi Ni
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Yu-Xin Chen
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Li Sheng
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Min Lian
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Can-Jie Guo
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Jing Hua
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| |
Collapse
|
|
33
|
Kaba S, Kawai Y, Tanigami Y, Ohnishi H, Kita T, Yoshimatsu M, Omori K, Kishimoto Y. Peroxisome Proliferator-Activated Receptor-γ Agonist Attenuates Vocal Fold Fibrosis in Rats via Regulation of Macrophage Activation. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:771-782. [PMID: 35189097 DOI: 10.1016/j.ajpath.2022.02.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 01/19/2022] [Accepted: 02/07/2022] [Indexed: 12/30/2022]
Abstract
Macrophages aid in wound healing by changing their phenotype and can be a key driver of fibrosis. However, the contribution of macrophage phenotype to fibrosis following vocal fold injury remains unclear. Peroxisome proliferator-activated receptor-γ (PPARγ) is expressed mainly by macrophages during early wound healing and regulates the macrophage phenotype. This study aimed to evaluate the effects of pioglitazone (PIO), a PPARγ agonist, on the macrophage phenotype and fibrosis following vocal fold injury in rats. PIO was injected into the rat vocal folds on days 1, 3, 5, and 7 after injury, and the vocal fold lamina propria was evaluated on days 4 and 56 after injury. Moreover, THP-1-derived macrophages were treated with PIO, and the expression of proinflammatory cytokines under lipopolysaccharide/interferon-γ stimulation was analyzed. PIO reduced the expression of Ccl2 both in vivo and in vitro. Furthermore, PIO decreased the density of inducible nitric oxide synthase+ CD68+ macrophages and inhibited the expression of fibrosis-related factors on day 4 after injury. On day 56 after injury, PIO inhibited fibrosis, tissue contracture, and hyaluronic acid loss in a PPARγ-dependent manner. These results indicate that PPARγ activation could inhibit accumulation of inflammatory macrophages and improve tissue repair. Taken together, these findings imply that inflammatory macrophages play a key role in vocal fold fibrosis.
Collapse
Affiliation(s)
- Shinji Kaba
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Otolaryngology, Kyoto Katsura Hospital, Kyoto, Japan
| | - Yoshitaka Kawai
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuki Tanigami
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroe Ohnishi
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoko Kita
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masayoshi Yoshimatsu
- Department of Otolaryngology, Head and Neck Surgery, Field of Sensory Organology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Koichi Omori
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yo Kishimoto
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| |
Collapse
|
|
34
|
Devan AR, Nair B, Kumar AR, Nath LR. An insight into the role of telmisartan as PPAR-γ/α dual activator in the management of nonalcoholic fatty liver disease. Biotechnol Appl Biochem 2022; 69:461-468. [PMID: 33578449 DOI: 10.1002/bab.2123] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 02/07/2021] [Indexed: 02/05/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease. It is rapidly emerging as the frequent cause for liver transplantation with the risk of disease recurrence, even after transplantation. Clinical evidence showed an abnormally altered expression of different peroxisome proliferator-activated receptor (PPAR) isotypes (PPAR-α/γ/δ) in NAFLD with an involvement in the induction of insulin resistance, hepatic steatosis, reactive oxygen species (ROS) formation, and hepatic inflammation. Recently, several dual PPAR-γ/α agonists were developed to simultaneously achieve the insulin-sensitizing effect of PPAR-γ as well as lipid catabolizing effect of PPAR-α. PPAR-α activation could counterbalance the steatogenic and adipogenic effects of PPAR-γ. But most of the drugs were ended in the initial level itself due to harmful adverse effects. In the present review, we discuss the possible mechanism of telmisartan, a typical angiotensin receptor blocker with excellent safety and pharmacokinetic profile, as a PPAR-γ/α dual agonist in the treatment of NAFLD.
Collapse
Affiliation(s)
- Aswathy R Devan
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
| | - Bhagyalakshmi Nair
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
| | - Ayana R Kumar
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
| | - Lekshmi R Nath
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
| |
Collapse
|
|
35
|
Puengel T, Liu H, Guillot A, Heymann F, Tacke F, Peiseler M. Nuclear Receptors Linking Metabolism, Inflammation, and Fibrosis in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23052668. [PMID: 35269812 PMCID: PMC8910763 DOI: 10.3390/ijms23052668] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/23/2022] [Accepted: 02/26/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) comprise a spectrum of chronic liver diseases in the global population that can lead to end-stage liver disease and hepatocellular carcinoma (HCC). NAFLD is closely linked to the metabolic syndrome, and comorbidities such as type 2 diabetes, obesity and insulin resistance aggravate liver disease, while NAFLD promotes cardiovascular risk in affected patients. The pathomechanisms of NAFLD are multifaceted, combining hepatic factors including lipotoxicity, mechanisms of cell death and liver inflammation with extrahepatic factors including metabolic disturbance and dysbiosis. Nuclear receptors (NRs) are a family of ligand-controlled transcription factors that regulate glucose, fat and cholesterol homeostasis and modulate innate immune cell functions, including liver macrophages. In parallel with metabolic derangement in NAFLD, altered NR signaling is frequently observed and might be involved in the pathogenesis. Therapeutically, clinical data indicate that single drug targets thus far have been insufficient for reaching patient-relevant endpoints. Therefore, combinatorial treatment strategies with multiple drug targets or drugs with multiple mechanisms of actions could possibly bring advantages, by providing a more holistic therapeutic approach. In this context, peroxisome proliferator-activated receptors (PPARs) and other NRs are of great interest as they are involved in wide-ranging and multi-organ activities associated with NASH progression or regression. In this review, we summarize recent advances in understanding the pathogenesis of NAFLD, focusing on mechanisms of cell death, immunometabolism and the role of NRs. We outline novel therapeutic strategies and discuss remaining challenges.
Collapse
Affiliation(s)
- Tobias Puengel
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
- Berlin Institute of Health (BIH), 10178 Berlin, Germany
| | - Hanyang Liu
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
| | - Adrien Guillot
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
| | - Felix Heymann
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
- Correspondence: (F.T.); (M.P.)
| | - Moritz Peiseler
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, 13353 Berlin, Germany; (T.P.); (H.L.); (A.G.); (F.H.)
- Berlin Institute of Health (BIH), 10178 Berlin, Germany
- Correspondence: (F.T.); (M.P.)
| |
Collapse
|
|
36
|
Alegre F, Martí-Rodrigo A, Polo M, Ortiz-Masiá D, Bañuls C, Pinti M, Álvarez Á, Apostolova N, Esplugues JV, Blas-García A. Macrophages Modulate Hepatic Injury Involving NLRP3 Inflammasome: The Example of Efavirenz. Biomedicines 2022; 10:biomedicines10010109. [PMID: 35052789 PMCID: PMC8772956 DOI: 10.3390/biomedicines10010109] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/22/2021] [Accepted: 12/30/2021] [Indexed: 02/04/2023] Open
Abstract
Drug-induced liver injury (DILI) constitutes a clinical challenge due to the incomplete characterization of the mechanisms involved and potential risk factors. Efavirenz, an anti-HIV drug, induces deleterious actions in hepatocytes that could underlie induction of the NLRP3 inflammasome, an important regulator of inflammatory responses during liver injury. We assessed the potential of efavirenz to modulate the inflammatory and fibrogenic responses of major liver cell types involved in DILI. The effects of efavirenz were evaluated both in vitro and in vivo. Efavirenz triggered inflammation in hepatocytes, in a process that involved NF-κB and the NLRP3 inflammasome, and activated hepatic stellate cells (HSCs), thereby enhancing expression of inflammatory and fibrogenic markers. The NLRP3 inflammasome was not altered in efavirenz-treated macrophages, but these cells polarized towards the anti-inflammatory M2 phenotype and displayed upregulated anti-inflammatory mediators. Conversely, no evidence of damage was observed in efavirenz-treated animals, except when macrophages were depleted, which resulted in the in vivo manifestation of the deleterious effects detected in hepatocytes and HSCs. Efavirenz elicits a cell-specific activation of the NLRP3 inflammasome in hepatocytes and HSCs, but macrophages appear to counteract efavirenz-induced liver injury. Our results highlight the dynamic nature of the interaction among liver cell populations and emphasize the potential of targeting macrophage polarization as a strategy to treat NLRP3 inflammasome-induced liver injury.
Collapse
Affiliation(s)
- Fernando Alegre
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Alberto Martí-Rodrigo
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Miriam Polo
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Dolores Ortiz-Masiá
- Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
| | - Celia Bañuls
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Marcello Pinti
- Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Ángeles Álvarez
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
| | - Nadezda Apostolova
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
| | - Juan V Esplugues
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
| | - Ana Blas-García
- Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
- Departamento de Fisiología, Universidad de Valencia, 46010 Valencia, Spain
| |
Collapse
|
|
37
|
Recent Advances in Adipose Tissue Dysfunction and Its Role in the Pathogenesis of Non-Alcoholic Fatty Liver Disease. Cells 2021; 10:cells10123300. [PMID: 34943809 PMCID: PMC8699427 DOI: 10.3390/cells10123300] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/09/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity is a serious ongoing health problem that significantly increases the incidence of nonalcoholic fatty liver disease (NAFLD). During obesity, adipose tissue dysfunction is obvious and characterized by increased fat deposition (adiposity) and chronic low-grade inflammation. The latter has been implicated to critically promote the development and progression of NAFLD, whose advanced form non-alcoholic steatohepatitis (NASH) is considered one of the most common causes of terminal liver diseases. This review summarizes the current knowledge on obesity-related adipose dysfunction and its roles in the pathogenesis of hepatic steatosis and inflammation, as well as liver fibrosis. A better understanding of the crosstalk between adipose tissue and liver under obesity is essential for the development of new and improved preventive and/or therapeutic approaches for managing NAFLD.
Collapse
|
|
38
|
Dong XC, Chowdhury K, Huang M, Kim HG. Signal Transduction and Molecular Regulation in Fatty Liver Disease. Antioxid Redox Signal 2021; 35:689-717. [PMID: 33906425 PMCID: PMC8558079 DOI: 10.1089/ars.2021.0076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Significance: Fatty liver disease is a major liver disorder in the modern societies. Comprehensive understanding of the pathophysiology and molecular mechanisms is essential for the prevention and treatment of the disease. Recent Advances: Remarkable progress has been made in the recent years in basic and translational research in the field of fatty liver disease. Multiple signaling pathways have been implicated in the development of fatty liver disease, including AMP-activated protein kinase, mechanistic target of rapamycin kinase, endoplasmic reticulum stress, oxidative stress, inflammation, transforming growth factor β, and yes1-associated transcriptional regulator/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). In addition, critical molecular regulations at the transcriptional and epigenetic levels have been linked to the pathogenesis of fatty liver disease. Critical Issues: Some critical issues remain to be solved so that research findings can be translated into clinical applications. Robust and reliable biomarkers are needed for diagnosis of different stages of the fatty liver disease. Effective and safe molecular targets remain to be identified and validated. Prevention strategies require solid scientific evidence and population-wide feasibility. Future Directions: As more data are generated with time, integrative approaches are needed to comprehensively understand the disease pathophysiology and mechanisms at multiple levels from population, organismal system, organ/tissue, to cell. The interactions between genes and environmental factors require deeper investigation for the purposes of prevention and personalized treatment of fatty liver disease. Antioxid. Redox Signal. 35, 689-717.
Collapse
Affiliation(s)
- Xiaocheng Charlie Dong
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, USA
| | - Kushan Chowdhury
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Menghao Huang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hyeong Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| |
Collapse
|
|
39
|
Sorg UR, Küpper N, Mock J, Tersteegen A, Petzsch P, Köhrer K, Hehlgans T, Pfeffer K. Lymphotoxin-β-receptor (LTβR) signaling on hepatocytes is required for liver regeneration after partial hepatectomy. Biol Chem 2021; 402:1147-1154. [PMID: 34087963 DOI: 10.1515/hsz-2021-0152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/27/2021] [Indexed: 11/15/2022]
Abstract
Lymphotoxin-β-receptor deficient (LTβR-/-) and Tumor Necrosis Factor Receptor p55 deficient (TNFRp55-/-) mice show defects in liver regeneration (LR) after partial hepatectomy (PHx) with significantly increased mortality. LTβR and TNFRp55 belong to the core members of the TNF/TNFR superfamily. Interestingly, combined failure of LTβR and TNFRp55 signaling after PHx leads to a complete defect in LR. Here, we first addressed the question which liver cell population crucially requires LTβR signaling for efficient LR. To this end, mice with a conditionally targeted LTβR allele (LTβRfl/fl) were crossed to AlbuminCre and LysozymeMCre mouse lines to unravel the function of the LTβR on hepatocytes and monocytes/macrophages/Kupffer cells, respectively. Analysis of these mouse lines clearly reveals that LTβR is required on hepatocytes for efficient LR while no deficit in LR was found in LTβRfl/fl × LysMCre mice. Second, the molecular basis for the cooperating role of LTβR and TNFRp55 signaling pathways in LR was investigated by transcriptome analysis of etanercept treated LTβR-/- (LTβR-/-/ET) mice. Bioinformatic analysis and subsequent verification by qRT-PCR identified novel target genes (Cyclin-L2, Fas-Binding factor 1, interferon-related developmental regulator 1, Leucyl-tRNA Synthetase 2, and galectin-4) that are upregulated by LTβR/TNFRp55 signaling after PHx and fail to be upregulated after PHx in LTβR-/-/ET mice.
Collapse
Affiliation(s)
- Ursula R Sorg
- Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Nicole Küpper
- Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Julia Mock
- Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Anne Tersteegen
- Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
- Current address: Institute of Biochemistry and Cell Biology, Otto von Guericke University, Leipziger Str. 44, D-39120 Magdeburg, Germany
| | - Patrick Petzsch
- Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich Heine University, Universitätsstraße 1, D-40225 Düsseldorf, Germany
| | - Karl Köhrer
- Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich Heine University, Universitätsstraße 1, D-40225 Düsseldorf, Germany
| | - Thomas Hehlgans
- Regensburg Center for Interventional Immunology (RCI), Regensburg University, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany
| | - Klaus Pfeffer
- Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| |
Collapse
|
|
40
|
Königshofer P, Brusilovskaya K, Petrenko O, Hofer BS, Schwabl P, Trauner M, Reiberger T. Nuclear Receptors in Liver Fibrosis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166235. [PMID: 34339839 DOI: 10.1016/j.bbadis.2021.166235] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/18/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
Nuclear receptors are ligand-activated transcription factors that regulate gene expression of a variety of key molecular signals involved in liver fibrosis. The primary cellular driver of liver fibrogenesis are activated hepatic stellate cells. Different NRs regulate the hepatic expression of pro-inflammatory and pro-fibrogenic cytokines that promote the transformation of hepatic stellate cells into fibrogenic myofibroblasts. Importantly, nuclear receptors regulate gene expression circuits that promote hepatic fibrogenesis and/or allow liver fibrosis regression. In this review, we highlight the direct and indirect influence of nuclear receptors on liver fibrosis, with a focus on hepatic stellate cells, and discuss potential therapeutic effects of nuclear receptor modulation in regard to anti-fibrotic and anti-inflammatory effects. Further research on nuclear receptors-related signaling may lead to the clinical development of effective anti-fibrotic therapies for patients with liver disease.
Collapse
Affiliation(s)
- Philipp Königshofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Ksenia Brusilovskaya
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Oleksandr Petrenko
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Benedikt Silvester Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
| |
Collapse
|
|
41
|
Best Practices and Progress in Precision-Cut Liver Slice Cultures. Int J Mol Sci 2021; 22:ijms22137137. [PMID: 34281187 PMCID: PMC8267882 DOI: 10.3390/ijms22137137] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/25/2021] [Accepted: 06/30/2021] [Indexed: 12/31/2022] Open
Abstract
Thirty-five years ago, precision-cut liver slices (PCLS) were described as a promising tool and were expected to become the standard in vitro model to study liver disease as they tick off all characteristics of a good in vitro model. In contrast to most in vitro models, PCLS retain the complex 3D liver structures found in vivo, including cell–cell and cell–matrix interactions, and therefore should constitute the most reliable tool to model and to investigate pathways underlying chronic liver disease in vitro. Nevertheless, the biggest disadvantage of the model is the initiation of a procedure-induced fibrotic response. In this review, we describe the parameters and potential of PCLS cultures and discuss whether the initially described limitations and pitfalls have been overcome. We summarize the latest advances in PCLS research and critically evaluate PCLS use and progress since its invention in 1985.
Collapse
|
|
42
|
Duran-Güell M, Flores-Costa R, Casulleras M, López-Vicario C, Titos E, Díaz A, Alcaraz-Quiles J, Horrillo R, Costa M, Fernández J, Arroyo V, Clària J. Albumin protects the liver from tumor necrosis factor α-induced immunopathology. FASEB J 2021; 35:e21365. [PMID: 33496031 DOI: 10.1096/fj.202001615rrr] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 12/26/2020] [Accepted: 12/28/2020] [Indexed: 11/11/2022]
Abstract
Besides its oncotic power, albumin exerts pleiotropic actions, including binding, transport, and detoxification of endogenous and exogenous molecules, antioxidant activity, and modulation of immune and inflammatory responses. In particular, recent studies have demonstrated that albumin reduces leukocyte cytokine production. Here, we investigated whether albumin also has the ability to protect tissues from the damaging actions of these inflammatory mediators. We circumscribed our investigation to tumor necrosis factor (TNF) α, which exemplifies the connection between immunity and tissue injury. In vivo experiments in analbuminemic mice showed that these mice exhibit a more pronounced response to a model of TNFα-mediated liver injury induced by the administration of lipopolysaccharide (LPS) and D-galactosamine (D-gal). A tissue protective action against LPS/D-gal liver injury was also observed during the administration of human albumin to humanized mice expressing the human genes for albumin and neonatal Fc receptor (hAlb+/+ /hFcRn+/+ ) with preestablished carbon tetrachloride (CCl4 )-induced early cirrhosis. The cytoprotective actions of albumin against TNFα-induced injury were confirmed ex vivo, in precision-cut liver slices, and in vitro, in primary hepatocytes in culture. Albumin protective actions were independent of its scavenging properties and were reproduced by recombinant human albumin expressed in Oryza sativa. Albumin cytoprotection against TNFα injury was related to inhibition of lysosomal cathepsin B leakage accompanied by reductions in mitochondrial cytochrome c release and caspase-3 activity. These data provide evidence that in addition to reducing cytokines, the albumin molecule also has the ability to protect tissues against inflammatory injury.
Collapse
Affiliation(s)
- Marta Duran-Güell
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.,Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, CIBERehd, Barcelona, Spain
| | - Roger Flores-Costa
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.,Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, CIBERehd, Barcelona, Spain
| | - Mireia Casulleras
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.,Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, CIBERehd, Barcelona, Spain
| | - Cristina López-Vicario
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.,Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, CIBERehd, Barcelona, Spain
| | - Esther Titos
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, CIBERehd, Barcelona, Spain.,Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain
| | - Alba Díaz
- Pathology Service, Hospital Clínic, Barcelona, Spain
| | - José Alcaraz-Quiles
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, CIBERehd, Barcelona, Spain
| | | | | | - Javier Fernández
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.,Liver Unit, Hospital Clínic, Barcelona, Spain
| | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain
| | - Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.,Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, CIBERehd, Barcelona, Spain.,Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
43
|
Zhang Y, Bobe G, Miranda CL, Lowry MB, Hsu VL, Lohr CV, Wong CP, Jump DB, Robinson MM, Sharpton TJ, Maier CS, Stevens JF, Gombart AF. Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ. eLife 2021; 10:e66398. [PMID: 34128467 PMCID: PMC8205491 DOI: 10.7554/elife.66398] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 05/18/2021] [Indexed: 12/13/2022] Open
Abstract
We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C57Bl/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated that TXN might antagonize lipogenic PPARγ actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A peroxisome proliferator activated receptor gamma (PPARγ) competitive binding assay showed that XN and TXN bind to PPARγ with an IC50 similar to pioglitazone and 8-10 times stronger than oleate. Molecular docking simulations demonstrated that XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.
Collapse
Affiliation(s)
- Yang Zhang
- School of Biological and Population Health Sciences, Nutrition Program, Linus Pauling Institute, Oregon State UniversityCorvallisUnited States
| | - Gerd Bobe
- Department of Animal Sciences, Linus Pauling Institute, Oregon State UniversityCorvallisUnited States
| | - Cristobal L Miranda
- Department of Pharmaceutical Sciences, Linus Pauling Institute, Oregon State UniversityCorvallisUnited States
| | - Malcolm B Lowry
- Department of Microbiology, Oregon State UniversityCorvallisUnited States
| | - Victor L Hsu
- Department of Biochemistry and Biophysics, Oregon State UniversityCorvallisUnited States
| | - Christiane V Lohr
- Department of Biomedical Science, Carlson College of Veterinary MedicineCorvallisUnited States
| | - Carmen P Wong
- School of Biological and Population Health Sciences, Nutrition Program, Linus Pauling Institute, Oregon State UniversityCorvallisUnited States
| | - Donald B Jump
- School of Biological and Population Health Sciences, Nutrition Program, Linus Pauling Institute, Oregon State UniversityCorvallisUnited States
| | - Matthew M Robinson
- School of Biological and Population Health Sciences, Kinesiology Program, Oregon State UniversityCorvallisUnited States
| | - Thomas J Sharpton
- Department of Microbiology, Department of Statistics, Oregon State UniversityCorvallisUnited States
| | - Claudia S Maier
- Department of Chemistry, Linus Pauling Institute, Oregon State UniversityCorvallisUnited States
| | - Jan F Stevens
- Department of Pharmaceutical Sciences, Linus Pauling Institute, Oregon State UniversityCorvallisUnited States
| | - Adrian F Gombart
- Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State UniversityCorvallisUnited States
| |
Collapse
|
|
44
|
Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis-Roles as Putative Treatment Targets? Biomedicines 2021; 9:biomedicines9040365. [PMID: 33807461 PMCID: PMC8066583 DOI: 10.3390/biomedicines9040365] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic fibrosis is the primary predictor of mortality in patients with non-alcoholic steatohepatitis (NASH). In this process, the activated hepatic stellate cells (HSCs) constitute the principal cells responsible for the deposition of a fibrous extracellular matrix, thereby driving the hepatic scarring. HSC activation, migration, and proliferation are controlled by a complex signaling network involving growth factors, lipotoxicity, inflammation, and cellular stress. Conversely, the clearance of activated HSCs is a prerequisite for the resolution of the extracellular fibrosis. Hence, pathways regulating the fate of the HSCs may represent attractive therapeutic targets for the treatment and prevention of NASH-associated hepatic fibrosis. However, the development of anti-fibrotic drugs for NASH patients has not yet resulted in clinically approved therapeutics, underscoring the complex biology and challenges involved when targeting the intricate cellular signaling mechanisms. This narrative review investigated the mechanisms of activation and inactivation of HSCs with a focus on NASH-associated hepatic fibrosis. Presenting an updated overview, this review highlights key cellular pathways with potential value for the development of future treatment modalities.
Collapse
|
|
45
|
Cariello M, Piccinin E, Moschetta A. Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH. Cell Mol Gastroenterol Hepatol 2021; 11:1519-1539. [PMID: 33545430 PMCID: PMC8042405 DOI: 10.1016/j.jcmgh.2021.01.012] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of NASH. In detail, we discuss the pros and cons of the putative transcriptional action of the fatty acid sensors (peroxisome proliferator-activated receptors), the bile acid sensor (farnesoid X receptor), and the oxysterol sensor (liver X receptors) in the pathogenesis and bona fide treatment of NASH.
Collapse
Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Elena Piccinin
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro," Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy; National Institute for Biostructures and Biosystems (INBB), Rome, Italy; Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy.
| |
Collapse
|
|
46
|
PPARs in liver physiology. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166097. [PMID: 33524529 DOI: 10.1016/j.bbadis.2021.166097] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and transcriptional modulators with crucial functions in hepatic and whole-body energy homeostasis. Besides their well-documented roles in lipid and glucose metabolism, emerging evidence also implicate PPARs in the control of other processes such as inflammatory responses. Recent technological advances, such as single-cell RNA sequencing, have allowed to unravel an unexpected complexity in the regulation of PPAR expression, activity and downstream signaling. Here we provide an overview of the latest advances in the study of PPARs in liver physiology, with a specific focus on formerly neglected aspects of PPAR regulation, such as tissular zonation, cellular heterogeneity, circadian rhythms, sexual dimorphism and species-specific features.
Collapse
|
|
47
|
Lee SM, Pusec CM, Norris GH, De Jesus A, Diaz-Ruiz A, Muratalla J, Sarmento-Cabral A, Guzman G, Layden BT, Cordoba-Chacon J. Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver. Cell Mol Gastroenterol Hepatol 2021; 11:1291-1311. [PMID: 33444819 PMCID: PMC8005819 DOI: 10.1016/j.jcmgh.2021.01.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARγ) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARγ plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH. METHODS Hepatocyte-specific PPARγ expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet. RESULTS HFCF diet increased PPARγ expression in hepatocytes, and rosiglitazone further activated PPARγ in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARγ reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARγ-dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARγ plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH. CONCLUSIONS Because of the negative effect of hepatocyte PPARγ in NASH, inhibition of mechanisms promoted by endogenous PPARγ in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD.
Collapse
Affiliation(s)
- Samuel M. Lee
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Carolina M. Pusec
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Gregory H. Norris
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | | | | | - Jose Muratalla
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Andre Sarmento-Cabral
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Brian T. Layden
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois,Research and Development, Jesse Brown VA Medical Center, Chicago, Illinois
| | - Jose Cordoba-Chacon
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois,Correspondence Address correspondence to: Jose Cordoba-Chacon, PhD, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, 835 South Wolcott Avenue (North Entrance), Suite E625, M/C 640, Chicago, Illinois 60612. fax (312) 413-0437.
| |
Collapse
|
|
48
|
Loupy KM, Cler KE, Marquart BM, Yifru TW, D'Angelo HM, Arnold MR, Elsayed AI, Gebert MJ, Fierer N, Fonken LK, Frank MG, Zambrano CA, Maier SF, Lowry CA. Comparing the effects of two different strains of mycobacteria, Mycobacterium vaccae NCTC 11659 and M. vaccae ATCC 15483, on stress-resilient behaviors and lipid-immune signaling in rats. Brain Behav Immun 2021; 91:212-229. [PMID: 33011306 PMCID: PMC7749860 DOI: 10.1016/j.bbi.2020.09.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/17/2020] [Accepted: 09/26/2020] [Indexed: 12/11/2022] Open
Abstract
Stress-related disorders, such as posttraumatic stress disorder (PTSD), are highly prevalent and often difficult to treat. In rodents, stress-related, anxiety-like defensive behavioral responses may be characterized by social avoidance, exacerbated inflammation, and altered metabolic states. We have previously shown that, in rodents, subcutaneous injections of a heat-killed preparation of the soil-derived bacterium Mycobacterium vaccae NCTC 11659 promotes stress resilience effects that are associated with immunoregulatory signaling in the periphery and the brain. In the current study, we sought to determine whether treatment with a heat-killed preparation of the closely related M. vaccae type strain, M. vaccae ATCC 15483, would also promote stress-resilience in adult male rats, likely due to biologically similar characteristics of the two strains. Here we show that immunization with either M. vaccae NCTC 11659 or M. vaccae ATCC 15483 prevents stress-induced increases in hippocampal interleukin 6 mRNA expression, consistent with previous studies showing that M. vaccae NCTC 11659 prevents stress-induced increases in peripheral IL-6 secretion, and prevents exaggeration of anxiety-like defensive behavioral responses assessed 24 h after exposure to inescapable tail shock stress (IS) in adult male rats. Analysis of mRNA expression, protein abundance, and flow cytometry data demonstrate overlapping but also unique effects of treatment with the two M. vaccae strains on immunological and metabolic signaling in the host. These data support the hypothesis that treatment with different M. vaccae strains may immunize the host against stress-induced dysregulation of physiology and behavior.
Collapse
Affiliation(s)
- Kelsey M Loupy
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Kristin E Cler
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Brandon M Marquart
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Tumim W Yifru
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Heather M D'Angelo
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Mathew R Arnold
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Ahmed I Elsayed
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Matthew J Gebert
- Department of Ecology and Evolutionary Biology, Cooperative Institute for Research in Environmental Sciences (CIRES), University of Colorado Boulder, Boulder, CO 80309, USA; Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Noah Fierer
- Department of Ecology and Evolutionary Biology, Cooperative Institute for Research in Environmental Sciences (CIRES), University of Colorado Boulder, Boulder, CO 80309, USA; Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Laura K Fonken
- Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX 78712, USA
| | - Matthew G Frank
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Cristian A Zambrano
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Steven F Maier
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Christopher A Lowry
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA; Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO 80309, USA; Department of Physical Medicine and Rehabilitation and Center for Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, CO 80045, USA; Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, CO 80045, USA; inVIVO Planetary Health, of the Worldwide Universities Network (WUN), West New York, NJ 07093, USA.
| |
Collapse
|
|
49
|
Diniz TA, de Lima Junior EA, Teixeira AA, Biondo LA, da Rocha LAF, Valadão IC, Silveira LS, Cabral-Santos C, de Souza CO, Rosa Neto JC. Aerobic training improves NAFLD markers and insulin resistance through AMPK-PPAR-α signaling in obese mice. Life Sci 2020; 266:118868. [PMID: 33310034 DOI: 10.1016/j.lfs.2020.118868] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/28/2020] [Accepted: 12/01/2020] [Indexed: 12/24/2022]
Abstract
Liver steatosis is one of the main drivers for the development of whole-body insulin resistance. Conversely, aerobic training (AT) has been suggested as non-pharmacological tool to improve liver steatosis, however, the underlying molecular mechanism remains unclear. Therefore, the aim of this study was to analyze the effect of 8-weeks AT in non-alcoholic liver disease (NAFLD) outcomes in obese mice. Male C57BL/6 J wild type (WT) were fed with standard (SD) or high-fat diet (HFD) for 12-weeks. Another group fed with HFD underwent 8-weeks of AT (60% of maximum velocity), initiated at the 5th week of experimental protocol. We measured metabolic, body composition parameters, protein and gene expression inflammatory and metabolic mediators. We found that AT attenuates the weight gain, but not body fat accumulation. AT improved triacylglycerol and non-esterified fatty acid plasma concentrations, and also whole-body insulin resistance. Regarding NAFLD, AT decreased the progression of macrovesicular steatosis and inflammation through the upregulation of AMPK Thr172 phosphorylation and PPAR-α protein expression. Moreover, although no effects of intervention in PPAR-γ protein concentration were observed, we found increased levels of its target genes Cd36 and Scd1 in exercised group, demonstrating augmented transcriptional activity. AT reduced liver cytokines concentrations, such as TNF-α, IL-10, MCP-1 and IL-6, regardless of increased Ser536 NF-κB phosphorylation. In fact, none of the interventions regulated NF-κB target genes Il1b and Cccl2, demonstrating its low transcriptional activity. Therefore, we conclude that AT attenuates the progression of liver macrovesicular steatosis and inflammation through AMPK-PPAR-α signaling and PPAR-γ activation, respectively, improving insulin resistance in obese mice.
Collapse
Affiliation(s)
- Tiego Aparecido Diniz
- Immunometabolism Research Group, Department of Cell and Developmental Biology, University of São Paulo, Avenida Prof Lineu Prestes, 1524, CEP 05508-900 Butantã, São Paulo, Brazil
| | - Edson Alves de Lima Junior
- Immunometabolism Research Group, Department of Cell and Developmental Biology, University of São Paulo, Avenida Prof Lineu Prestes, 1524, CEP 05508-900 Butantã, São Paulo, Brazil
| | - Alexandre Abílio Teixeira
- Immunometabolism Research Group, Department of Cell and Developmental Biology, University of São Paulo, Avenida Prof Lineu Prestes, 1524, CEP 05508-900 Butantã, São Paulo, Brazil
| | - Luana Amorim Biondo
- Immunometabolism Research Group, Department of Cell and Developmental Biology, University of São Paulo, Avenida Prof Lineu Prestes, 1524, CEP 05508-900 Butantã, São Paulo, Brazil
| | | | | | - Loreana Sanches Silveira
- Immunometabolism Research Group, Department of Cell and Developmental Biology, University of São Paulo, Avenida Prof Lineu Prestes, 1524, CEP 05508-900 Butantã, São Paulo, Brazil
| | - Carol Cabral-Santos
- Exercise and Immunometabolism Research Group, Department of Physical Education, University of the State of Sao Paulo, Rua Roberto Simonsen, 305, 19060-900 Presidente Prudente, SP, Brazil
| | - Camila Oliveira de Souza
- Immunometabolism Research Group, Department of Cell and Developmental Biology, University of São Paulo, Avenida Prof Lineu Prestes, 1524, CEP 05508-900 Butantã, São Paulo, Brazil
| | - José Cesar Rosa Neto
- Immunometabolism Research Group, Department of Cell and Developmental Biology, University of São Paulo, Avenida Prof Lineu Prestes, 1524, CEP 05508-900 Butantã, São Paulo, Brazil.
| |
Collapse
|
|
50
|
Ni XX, Li XY, Wang Q, Hua J. Regulation of peroxisome proliferator-activated receptor-gamma activity affects the hepatic stellate cell activation and the progression of NASH via TGF-β1/Smad signaling pathway. J Physiol Biochem 2020; 77:35-45. [PMID: 33188625 DOI: 10.1007/s13105-020-00777-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023]
Abstract
Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (activated HSCs), which produce excessive extracellular matrix. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) exerts protective effects on hepatic inflammation and fibrosis. The current study was to explore the function of PPAR-γ on HSC activation and progression of nonalcoholic steatohepatitis (NASH). Our study found that HSCs were gradually activated during the progression of methionine-choline-deficient (MCD) diet-induced NASH, accompanied by decreased PPAR-γ expression and activated TGF-β1/Smad signaling pathway in the liver. PPAR-γ agonist was found to inhibit primary HSCs and NIH/3T3 fibroblast activation and reverted their phenotypical morphology induced by TGF-β1 in vitro. In addition to this, PPAR-γ agonist decreased expression of TGF-β1 and phosphorylation of Smad2/3 while increased expression of Smad7. In vivo, rosiglitazone, a PPAR-γ agonist, inhibited HSC activation and alleviated liver fibrosis and inflammation similarly via inhibiting the activation of TGF-β1/Smad signaling pathway. In parallel, rosiglitazone alleviated hepatic lipid accumulation and peroxidation, beneficial to reverse of NASH. From these findings, it can be concluded that the gradual activation of HSCs is crucial to the progression of NASH and modulating PPAR-γ expression can affect HSC activation via TGF-β1/Smad signaling pathway and thereby influence hepatic fibrogenesis.
Collapse
Affiliation(s)
- Xi-Xi Ni
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, People's Republic of China
| | - Xiao-Yun Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, People's Republic of China
| | - Qi Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, People's Republic of China
| | - Jing Hua
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pu Jian Road, Shanghai, 200127, People's Republic of China.
| |
Collapse
|