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Choudhuri S, Garg NJ. Hepatocyte Nuclear Factor 4 Alpha: A Key Regulator of Liver Disease Pathology and Haemostatic Disorders. Liver Int 2025; 45:e16245. [PMID: 40387433 DOI: 10.1111/liv.16245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/19/2024] [Accepted: 01/03/2025] [Indexed: 05/20/2025]
Abstract
OBJECTIVE Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte differentiation in fetal and adult liver and exerts its transcriptional role in determining physiological functions of the liver. The objective of this review is to address the current knowledge of molecular mechanisms involved in HNF4α regulation in multiple aspects of liver disease pathogenesis. METHODS Based on available literature, this review summarises the current state of knowledge onthe mechanism of HNF4α dysregulation, and the role of HNF4α activity inregulating early to advanced stages of various liver diseases. RESULTS Patients with deranged HNF4α expression are at higher risk for the development of liver diseases such as viral hepatitis, alcoholic/nonalcoholic fatty liver disease, hepatocellular carcinoma, and haematological disorders such as coagulopathy and bleeding disorders. DISCUSSION HNF4α interactions with nuclear receptors and target genes promote liver disease pathology by regulating various metabolic pathways. The strong correlation between deranged HNF4α expression and the severity of liver diseases suggests that targeting HNF4α expression can offer potential therapeutic strategy in the prevention of liver disease pathology and haemostatic disorders.
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Affiliation(s)
- Subhadip Choudhuri
- Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA
- Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch (UTMB), Galveston, Texas, USA
| | - Nisha Jain Garg
- Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, USA
- Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch (UTMB), Galveston, Texas, USA
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Kulshrestha S, Karnik R, Vohra A, Joshi A, Devkar R. Melatonin partially restores hepatic nocturnin oscillations in experimental models of MASLD. Chronobiol Int 2025:1-14. [PMID: 40313203 DOI: 10.1080/07420528.2025.2496347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 03/12/2025] [Accepted: 04/16/2025] [Indexed: 05/03/2025]
Abstract
Melatonin, a pleiotropic neurohormone, is recognized for its hepatoprotective role in metabolic dysfunction-associated steatotic liver disease (MASLD) triggered by diet and/or chronodisruption. Nocturnin (Noct), a circadian clock output regulating hepatic lipid metabolism, has an unclear role in MASLD. This study explores circadian oscillations of Noct in MASLD and its synergy with melatonin. Differential gene expression analysis identified key lipogenic genes (HNF-4A and SCD) as targets of Noct enzymatic activity. Male C57BL/6J mice were subjected to high-fat-high-fructose (H) diet with or without chronodisruption (CD) for 16 weeks. Noct mRNA peaked at ZT12 in Control and H groups, while CD and HCD groups showed peaks at ZT6, alongside increased % relative amplitude, cumulative expression, and shifted Centre of Gravity (CoG). Melatonin treatment in H, CD, and HCD groups significantly reduced Noct amplitude and cumulative expression. In OA-treated HepG2 cells, Noct mRNA and protein levels rose at 36 h and 32 h, respectively, with CoG shifts. Melatonin reduced Noct mRNA but increased protein levels while correcting rhythmicity. Collectively, MASLD induces elevation and phase shifts in hepatic Noct expression, and melatonin demonstrates corrective effects on Noct circadian phasing, underscoring its therapeutic potential. .
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Affiliation(s)
- Shruti Kulshrestha
- Chronobiology and Metabolic Endocrinology Lab, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Rhydham Karnik
- Chronobiology and Metabolic Endocrinology Lab, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
- Dr. Vikram Sarabhai Institute of Cell and Molecular Biology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Aliasgar Vohra
- Chronobiology and Metabolic Endocrinology Lab, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
- Department of Neurology, School of Medicine, Washington University, St. Louis, Missouri, USA
| | - Apeksha Joshi
- Chronobiology and Metabolic Endocrinology Lab, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Ranjitsinh Devkar
- Chronobiology and Metabolic Endocrinology Lab, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
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Zeng C, Wei M, Li H, Yu L, Wang C, Mu Z, Huang Z, Ke Y, Li LY, Xiao Y, Wu M, Chen MK. Identification of IL-34 and Slc7al as potential key regulators in MASLD progression through epigenomic profiling. Epigenomics 2025; 17:281-295. [PMID: 39956835 PMCID: PMC11970744 DOI: 10.1080/17501911.2025.2467028] [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: 10/15/2024] [Accepted: 02/11/2025] [Indexed: 02/18/2025] Open
Abstract
OBJECTIVE Epigenetic alterations are critical regulators in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the dynamic epigenomic landscapes are not well defined. Our previous study found that H3K27ac and H3K9me3 play important roles in regulating lipid metabolic pathways in the early stages of MASLD. However, the epigenomic status in the inflammation stages still needs to be determined. METHOD C57BL/6 male mice were fed with the methionine- and choline-deficient (MCD) or normal diet, and their serum and liver samples were collected after 6 weeks. Serum alanine aminotransferase (ALT), aspartate amino transferase (AST), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were measured. Chromatin immunoprecipitation sequencing (ChIP-Seq) for H3K27ac and H3K9me3 was performed together with RNA sequencing (RNA-seq) and key regulators were analyzed. RESULTS The target genes of enhancers with increased H3K27ac and decreased H3K9me3 signals are enriched in lipid metabolism and immuno-inflammatory pathways. Il-34 and Slc7al are identified as potential regulators in MASLD. CONCLUSION Our study reveals that active enhancers and heterochromatin associated with metabolic and inflammatory genes are extensively reprogrammed in MCD-diet mice, and Il-34 and Slc7al are potentially key genes regulating the progression of MASLD.
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Affiliation(s)
- Chuanfei Zeng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Mingliang Wei
- Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Taikang Center for Life and Medical Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Huan Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Linxin Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Chuang Wang
- Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Taikang Center for Life and Medical Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Ziqi Mu
- Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Taikang Center for Life and Medical Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Ziyin Huang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Yujia Ke
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Lian-Yun Li
- Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Taikang Center for Life and Medical Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Yong Xiao
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Min Wu
- Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Taikang Center for Life and Medical Sciences, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Ming-Kai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
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Liu Z, Zhu H, Zhao J, Yu L, Que S, Xu J, Geng L, Zhou L, Valenti L, Zheng S. Multi-omics analysis reveals a crosstalk between ferroptosis and peroxisomes on steatotic graft failure after liver transplantation. MedComm (Beijing) 2024; 5:e588. [PMID: 38868330 PMCID: PMC11167151 DOI: 10.1002/mco2.588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 04/17/2024] [Accepted: 04/25/2024] [Indexed: 06/14/2024] Open
Abstract
To identify the mechanism underlying macrosteatosis (MaS)-related graft failure (GF) in liver transplantation (LT) by multi-omics network analysis. The transcriptome and metabolome were assayed in graft and recipient plasma in discovery (n = 68) and validation (n = 89) cohorts. Differentially expressed molecules were identified by MaS and GF status. Transcriptional regulatory networks were generated to explore the mechanism for MaS-related inferior post-transplant prognosis. The differentially expressed molecules associated with MaS and GF were enriched in ferroptosis and peroxisome-related pathways. Core features of MaS-related GF were presented on decreased transferrin and impaired anti-oxidative capacity dependent upon dysregulation of transcription factors hepatocyte nuclear factor 4A (HNF4A) and hypoxia-inducible factor 1A (HIF1A). Furthermore, miR-362-3p and miR-299-5p inhibited transferrin and HIF1A expression, respectively. Lower M2 macrophages but higher memory CD4 T cells were observed in MaS-related GF cases. These results were validated in clinical specimens and cellular models. Systemic analysis of multi-omics data depicted a panorama of biological pathways deregulated in MaS-related GF. Transcriptional regulatory networks centered on transferrin and anti-oxidant responses were associated with poor MaS graft quality, qualifying as potential targets to improve prognosis of patients after LT.
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Affiliation(s)
- Zhengtao Liu
- Shulan International Medical CollegeZhejiang Shuren UniversityHangzhouChina
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang ProvinceShulan International Medical CollegeZhejiang Shuren UniversityHangzhouChina
- NHC Key Laboratory of Combined Multi‐Organ TransplantationKey Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMS, First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Organ TransplantationFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Shulan Hospital (Hangzhou)HangzhouChina
| | - Hai Zhu
- NHC Key Laboratory of Combined Multi‐Organ TransplantationKey Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMS, First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Organ TransplantationFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Guangxi Medical UniversityNanningChina
| | - Junsheng Zhao
- Shulan International Medical CollegeZhejiang Shuren UniversityHangzhouChina
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang ProvinceShulan International Medical CollegeZhejiang Shuren UniversityHangzhouChina
| | - Lu Yu
- Shulan International Medical CollegeZhejiang Shuren UniversityHangzhouChina
- Shulan Hospital (Hangzhou)HangzhouChina
- School of MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | | | - Jun Xu
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of SurgeryFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Lei Geng
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of SurgeryFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Lin Zhou
- NHC Key Laboratory of Combined Multi‐Organ TransplantationKey Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMS, First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Organ TransplantationFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of SurgeryFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Luca Valenti
- Department of Pathophysiology and TransplantationUniversità degli Studi di MilanoMilanItaly
- Transfusion Medicine UnitFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
- Biological Resource Center UnitFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
| | - Shusen Zheng
- Shulan International Medical CollegeZhejiang Shuren UniversityHangzhouChina
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang ProvinceShulan International Medical CollegeZhejiang Shuren UniversityHangzhouChina
- NHC Key Laboratory of Combined Multi‐Organ TransplantationKey Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMS, First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Organ TransplantationFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Shulan Hospital (Hangzhou)HangzhouChina
- Division of Hepatobiliary and Pancreatic SurgeryDepartment of SurgeryFirst Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
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Dai L, Yuan W, Jiang R, Zhan Z, Zhang L, Xu X, Qian Y, Yang W, Zhang Z. Machine learning-based integration identifies the ferroptosis hub genes in nonalcoholic steatohepatitis. Lipids Health Dis 2024; 23:23. [PMID: 38263097 PMCID: PMC10804801 DOI: 10.1186/s12944-023-01988-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/11/2023] [Indexed: 01/25/2024] Open
Abstract
BACKGROUND Ferroptosis, is characterized by lipid peroxidation of fatty acids in the presence of iron ions, which leads to cell apoptosis. This leads to the disruption of metabolic pathways, ultimately resulting in liver dysfunction. Although ferroptosis is linked to nonalcoholic steatohepatitis (NASH), understanding the key ferroptosis-related genes (FRGs) involved in NASH remains incomplete. NASH may be targeted therapeutically by identifying the genes responsible for ferroptosis. METHODS To identify ferroptosis-related genes and develop a ferroptosis-related signature (FeRS), 113 machine-learning algorithm combinations were used. RESULTS The FeRS constructed using the Generalized Linear Model Boosting algorithm and Gradient Boosting Machine algorithms exhibited the best prediction performance for NASH. Eight FRGs, with ZFP36 identified by the algorithms as the most crucial, were incorporated into in FeRS. ZFP36 is significantly enriched in various immune cell types and exhibits significant positive correlations with most immune signatures. CONCLUSION ZFP36 is a key FRG involved in NASH pathogenesis.
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Affiliation(s)
- Longfei Dai
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Wenkang Yuan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Renao Jiang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Zhicheng Zhan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Liangliang Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Xinjian Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Yuyang Qian
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Wenqi Yang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China
| | - Zhen Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui Province, China.
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Sun Q, Xing X, Wang H, Wan K, Fan R, Liu C, Wang Y, Wu W, Wang Y, Wang R. SCD1 is the critical signaling hub to mediate metabolic diseases: Mechanism and the development of its inhibitors. Biomed Pharmacother 2024; 170:115586. [PMID: 38042113 DOI: 10.1016/j.biopha.2023.115586] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 09/23/2023] [Accepted: 09/25/2023] [Indexed: 12/04/2023] Open
Abstract
Metabolic diseases, featured with dysregulated energy homeostasis, have become major global health challenges. Patients with metabolic diseases have high probability to manifest multiple complications in lipid metabolism, e.g. obesity, insulin resistance and fatty liver. Therefore, targeting the hub genes in lipid metabolism may systemically ameliorate the metabolic diseases, along with the complications. Stearoyl-CoA desaturase 1(SCD1) is a key enzyme that desaturates the saturated fatty acids (SFAs) derived from de novo lipogenesis or diet to generate monounsaturated fatty acids (MUFAs). SCD1 maintains the metabolic and tissue homeostasis by responding to, and integrating the multiple layers of endogenous stimuli, which is mediated by the synthesized MUFAs. It critically regulates a myriad of physiological processes, including energy homeostasis, development, autophagy, tumorigenesis and inflammation. Aberrant transcriptional and epigenetic activation of SCD1 regulates AMPK/ACC, SIRT1/PGC1α, NcDase/Wnt, etc, and causes aberrant lipid accumulation, thereby promoting the progression of obesity, non-alcoholic fatty liver, diabetes and cancer. This review critically assesses the integrative mechanisms of the (patho)physiological functions of SCD1 in metabolic homeostasis, inflammation and autophagy. For translational perspective, potent SCD1 inhibitors have been developed to treat various types of cancer. We thus discuss the multidisciplinary advances that greatly accelerate the development of SCD1 new inhibitors. In conclusion, besides cancer treatment, SCD1 may serve as the promising target to combat multiple metabolic complications simultaneously.
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Affiliation(s)
- Qin Sun
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Xiaorui Xing
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Huanyu Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Kang Wan
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Ruobing Fan
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Cheng Liu
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Yongjian Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Wenyi Wu
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Yibing Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China.
| | - Ru Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China.
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Pan C, Liu J, Gao Y, Yang M, Hu H, Liu C, Qian M, Yuan HY, Yang S, Zheng MH, Wang L. Hepatocyte CHRNA4 mediates the MASH-promotive effects of immune cell-produced acetylcholine and smoking exposure in mice and humans. Cell Metab 2023; 35:2231-2249.e7. [PMID: 38056431 DOI: 10.1016/j.cmet.2023.10.018] [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: 06/21/2023] [Revised: 09/28/2023] [Accepted: 11/01/2023] [Indexed: 12/08/2023]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a leading risk factor for liver cirrhosis and hepatocellular carcinoma. Here, we report that CHRNA4, a subunit of nicotinic acetylcholine receptors (nAChRs), is an accelerator of MASH progression. CHRNA4 also mediates the MASH-promotive effects induced by smoking. Chrna4 was expressed specifically in hepatocytes and exhibited increased levels in mice and patients with MASH. Elevated CHRNA4 levels were positively correlated with MASH severity. We further revealed that during MASH development, acetylcholine released from immune cells or nicotine derived from smoking functioned as an agonist to activate hepatocyte-intrinsic CHRNA4, inducing calcium influx and activation of inflammatory signaling. The communication between immune cells and hepatocytes via the acetylcholine-CHRNA4 axis led to the production of a variety of cytokines, eliciting inflammation in liver and promoting the pathogenesis of MASH. Genetic and pharmacological inhibition of CHRNA4 protected mice from diet-induced MASH. Targeting CHRNA4 might be a promising strategy for MASH therapeutics.
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Affiliation(s)
- Chuyue Pan
- Institute of Modern Biology, Nanjing University, Nanjing 210008, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiang Su 211198, China
| | - Jun Liu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiang Su 211198, China
| | - Yingsheng Gao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiang Su 211198, China
| | - Maohui Yang
- Institute of Modern Biology, Nanjing University, Nanjing 210008, China
| | - Haiyang Hu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiang Su 211198, China
| | - Chang Liu
- Institute of Modern Biology, Nanjing University, Nanjing 210008, China
| | - Minyi Qian
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiang Su 211198, China
| | - Hai-Yang Yuan
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Song Yang
- Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing 100015, China.
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
| | - Lirui Wang
- Institute of Modern Biology, Nanjing University, Nanjing 210008, China.
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Ma SR, Ma Q, Ma YN, Zhou WJ. Comprehensive analysis of ceRNA network composed of circRNA, miRNA, and mRNA in septic acute kidney injury patients based on RNA-seq. Front Genet 2023; 14:1209042. [PMID: 37779910 PMCID: PMC10538531 DOI: 10.3389/fgene.2023.1209042] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/30/2023] [Indexed: 10/03/2023] Open
Abstract
Background: Sepsis is a complex, life-threatening clinical syndrome that can cause other related diseases, such as acute kidney injury (AKI). Circular RNA (circRNA) is a type of non-coding RNA with a diverse range of functions, and it plays essential roles in miRNA sponge. CircRNA plays a huge part in the development of various diseases. CircRNA and the competing endogenous RNA (ceRNA) regulatory network are unknown factors in the onset and progression of septic AKI (SAKI). This study aimed to clarify the complex circRNA-associated regulatory mechanism of circRNAs in SAKI. Methods: We collected 40 samples of whole blood of adults, including 20 cases of SAKI and 20 cases of healthy controls. Moreover, five cases were each analyzed by RNA sequencing, and we identified differentially expressed circRNA, miRNA, and mRNA (DEcircRNAs, DEmiRNAs, and DEmRNAs, respectively). All samples were from SAKI patients with intraperitoneal infection. Results: As a result, we screened out 236 DEcircRNAs, 105 DEmiRNAs, and 4065 DEmRNAs. Then, we constructed two co-expression networks based on RNA-RNA interaction, including circRNA-miRNA and miRNA-mRNA co-expression networks. We finally created a circRNA-miRNA-mRNA regulation network by combining the two co-expression networks. Functional and pathway analyses indicated that DEmRNAs in ceRNA were mostly concentrated in T cell activation, neutrophils and their responses, and cytokines. The protein-protein interaction network was established to screen out the key genes participating in the regulatory network of SAKI. The hub genes identified as the top 10 nodes included the following: ZNF727, MDFIC, IFITM2, FOXD4L6, CIITA, KCNE1B, BAGE2, PPIAL4A, USP17L7, and PRSS2. Conclusion: To our knowledge, this research is the first study to describe changes in the expression profiles of circRNAs, miRNAs, and mRNAs in patients with SAKI. These findings provide a new treatment target for SAKI treatment and novel ideas for its pathogenesis.
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Affiliation(s)
- Si-Rong Ma
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Qi Ma
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Ya-Nan Ma
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Wen-Jie Zhou
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
- Department of Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan, China
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Ghosh S, Devereaux MW, Orlicky DJ, Sokol RJ. Pharmacologic inhibition of HNF4α prevents parenteral nutrition associated cholestasis in mice. Sci Rep 2023; 13:7752. [PMID: 37173326 PMCID: PMC10182080 DOI: 10.1038/s41598-023-33994-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Prolonged parenteral nutrition (PN) can lead to PN associated cholestasis (PNAC). Intestinally derived lipopolysaccharides and infused PN phytosterols lead to activation of NFκB, a key factor in PNAC. Our objective was to determine if inhibition of HNF4α could interfere with NFκB to alleviate murine PNAC. We showed that HNF4α antagonist BI6015 (20 mg/kg/day) in DSS-PN (oral DSS x4d followed by Total PN x14d) mice prevented the increased AST, ALT, bilirubin and bile acids and reversed mRNA suppression of hepatocyte Abcg5/8, Abcb11, FXR, SHP and MRP2 that were present during PNAC. Further, NFκB phosphorylation in hepatocytes and its binding to LRH-1 and BSEP promoters in liver, which are upregulated in DSS-PN mice, were inhibited by BI6015 treatment. BI6015 also prevented the upregulation in liver macrophages of Adgre1 (F4/80) and Itgam (CD11B) that occurs in DSS-PN mice, with concomitant induction of anti-inflammatory genes (Klf2, Klf4, Clec7a1, Retnla). In conclusion, HNF4α antagonism attenuates PNAC by suppressing NFκB activation and signaling while inducing hepatocyte FXR and LRH-1 and their downstream bile and sterol transporters. These data identify HNF4α antagonism as a potential therapeutic target for prevention and treatment of PNAC.
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Affiliation(s)
- Swati Ghosh
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 E. 16th Ave, Aurora, CO, 80045, USA
| | - Michael W Devereaux
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 E. 16th Ave, Aurora, CO, 80045, USA
| | - David J Orlicky
- Department of Pathology, University of Colorado School of Medicine, 12801, E 17th Ave, Aurora, CO, 80045, USA
| | - Ronald J Sokol
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 E. 16th Ave, Aurora, CO, 80045, USA.
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10
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Abstract
Hepatocyte nuclear factor 4 α (HNF4α) is a highly conserved member of the nuclear receptor superfamily expressed at high levels in the liver, kidney, pancreas, and gut. In the liver, HNF4α is exclusively expressed in hepatocytes, where it is indispensable for embryonic and postnatal liver development and for normal liver function in adults. It is considered a master regulator of hepatic differentiation because it regulates a significant number of genes involved in hepatocyte-specific functions. Loss of HNF4α expression and function is associated with the progression of chronic liver disease. Further, HNF4α is a target of chemical-induced liver injury. In this review, we discuss the role of HNF4α in liver pathophysiology and highlight its potential use as a therapeutic target for liver diseases.
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Affiliation(s)
- Manasi Kotulkar
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Dakota R Robarts
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Udayan Apte
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
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11
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Kasano-Camones CI, Takizawa M, Ohshima N, Saito C, Iwasaki W, Nakagawa Y, Fujitani Y, Yoshida R, Saito Y, Izumi T, Terawaki SI, Sakaguchi M, Gonzalez FJ, Inoue Y. PPARα activation partially drives NAFLD development in liver-specific Hnf4a-null mice. J Biochem 2023; 173:393-411. [PMID: 36779417 PMCID: PMC10433406 DOI: 10.1093/jb/mvad005] [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: 09/19/2022] [Accepted: 01/13/2023] [Indexed: 01/24/2023] Open
Abstract
HNF4α regulates various genes to maintain liver function. There have been reports linking HNF4α expression to the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. In this study, liver-specific Hnf4a-deficient mice (Hnf4aΔHep mice) developed hepatosteatosis and liver fibrosis, and they were found to have difficulty utilizing glucose. In Hnf4aΔHep mice, the expression of fatty acid oxidation-related genes, which are PPARα target genes, was increased in contrast to the decreased expression of PPARα, suggesting that Hnf4aΔHep mice take up more lipids in the liver instead of glucose. Furthermore, Hnf4aΔHep/Ppara-/- mice, which are simultaneously deficient in HNF4α and PPARα, showed improved hepatosteatosis and fibrosis. Increased C18:1 and C18:1/C18:0 ratio was observed in the livers of Hnf4aΔHep mice, and the transactivation of PPARα target gene was induced by C18:1. When the C18:1/C18:0 ratio was close to that of Hnf4aΔHep mouse liver, a significant increase in transactivation was observed. In addition, the expression of Pgc1a, a coactivator of PPARs, was increased, suggesting that elevated C18:1 and Pgc1a expression could contribute to PPARα activation in Hnf4aΔHep mice. These insights may contribute to the development of new diagnostic and therapeutic approaches for NAFLD by focusing on the HNF4α and PPARα signaling cascade.
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Affiliation(s)
- Carlos Ichiro Kasano-Camones
- Laboratory of Metabolism, Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan
| | - Masayuki Takizawa
- Laboratory of Metabolism, Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan
| | - Noriyasu Ohshima
- Department of Biochemistry, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan
| | - Chinatsu Saito
- Laboratory of Metabolism, Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan
| | - Wakana Iwasaki
- Laboratory of Metabolism, Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan
| | - Yuko Nakagawa
- Laboratory of Developmental Biology and Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan
| | - Yoshio Fujitani
- Laboratory of Developmental Biology and Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan
| | - Ryo Yoshida
- Laboratory of Metabolism, Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan
| | - Yoshifumi Saito
- Laboratory of Metabolism, Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan
| | - Takashi Izumi
- Department of Biochemistry, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan
- Faculty of Health Care, Teikyo Heisei University, Tokyo 170-8445, Japan
| | - Shin-Ichi Terawaki
- Laboratory of Metabolism, Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan
| | - Masakiyo Sakaguchi
- Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20852, USA
| | - Yusuke Inoue
- Laboratory of Metabolism, Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan
- Gunma University Center for Food Science and Wellness, Maebashi, Gunma 371-8510, Japan
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12
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Bhat M, Pasini E, Patel P, Yu J, Baciu C, Kurian SM, Levitsky J. Achieving tolerance modifies cancer susceptibility profiles in liver transplant recipients. Cancer Med 2023; 12:5150-5157. [PMID: 36205189 PMCID: PMC9972022 DOI: 10.1002/cam4.5271] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 11/11/2022] Open
Abstract
Long-term survival of transplant recipients is significantly impacted by malignancy. We aimed to determine whether calcineurin inhibitor (CNI)-treated recipients converted to and weaned off molecular target of rapamycin inhibitor (mTOR-I) therapy have favorable changes in their molecular profiles in regard to malignancy risk. We performed gene expression profiling from liver biopsy and blood (PBMC) specimens followed by network analysis of key dysregulated genes, associated diseases and disorders, molecular and cellular functions using IPA software. Twenty non-immune, non-viremic patients were included, and 8 of them achieved tolerance. Two comparisons were performed: (1) tolerance time point vs tacrolimus monotherapy and (2) tolerance time point vs sirolimus monotherapy. Upon achieving tolerance, IPA predicted significant activation of DNA damage response (p = 5.40e-04) and inhibition of DNA replication (p = 7.56e-03). Conversion from sirolimus to tolerance showed decrease in HCC (p = 1.30e-02), hepatic steatosis (p = 5.60e-02) and liver fibrosis (p = 2.91e-02) associated genes. In conclusion, this longitudinal study of patients eventually achieving tolerance reveals an evolving molecular profile associated with decreased cancer risk and improved hepatic steatosis and liver fibrosis. This provides a biological rationale for attempting conversion to mTOR-I therapy and tolerance following liver transplantation particularly in patients at higher risk of cancer incidence and progression post-transplant.
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Affiliation(s)
- Mamatha Bhat
- Multi Organ Transplant Program and Division of GastroenterologyUniversity Health Network and University of TorontoTorontoCanada
| | - Elisa Pasini
- Multi Organ Transplant Program and Division of GastroenterologyUniversity Health Network and University of TorontoTorontoCanada
| | - Preya Patel
- Multi Organ Transplant Program and Division of GastroenterologyUniversity Health Network and University of TorontoTorontoCanada
| | - Jeffrey Yu
- Multi Organ Transplant Program and Division of GastroenterologyUniversity Health Network and University of TorontoTorontoCanada
| | - Cristina Baciu
- Multi Organ Transplant Program and Division of GastroenterologyUniversity Health Network and University of TorontoTorontoCanada
| | - Sunil M. Kurian
- Scripps Clinic Bio‐Repository & Transplantation Research, Scripps Clinic & Green HospitalLa JollaCaliforniaUSA
| | - Josh Levitsky
- Division of Gastroenterology & Hepatology, Department of MedicineNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
- Comprehensive Transplant Center, Department of SurgeryNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
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13
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Younes M, Zhang L, Fekry B, Eckel-Mahan K. Expression of p-STAT3 and c-Myc correlates with P2-HNF4α expression in nonalcoholic fatty liver disease (NAFLD). Oncotarget 2022; 13:1308-1313. [PMID: 36473131 PMCID: PMC9726203 DOI: 10.18632/oncotarget.28324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
We studied the expression of two hepatocyte nuclear factor 4 alpha (HNF4α) isoforms, p-STAT3. and c-Myc in 49 consecutive liver biopsies with nonalcoholic fatty liver disease (NAFLD) using immunohistochemistry. All 49 biopsies (100%) were positive for nuclear expression of P1-HNF4α. Twenty-eight (57%) cases were positive for P2-HNF4α, 6 (12%) were positive for p-STAT3 and 5 (10%) were positive for c-Myc. All 6 (100%) p-STAT3-positive cases were also positive for P2-HNF4α (p = 0.03). p-STAT3-positive cases were more likely to be positive for c-Myc (67% vs. 2%, p = 0.0003). Four cases were positive for P2-HNF4α, p-STAT3 and c-Myc. p-STAT3 expression was associated with hypertension (p = 0.037). All c-Myc positive biopsies were from patients with obesity, diabetes and hypertension. Only c-Myc expression was associated with advanced fibrosis; three (60%) of the c-Myc positive cases were associated with advanced fibrosis in contrast to 7 (10%) of the 44 c-Myc negative cases (p = 0.011). Based on these results, we hypothesize with the following sequence of events with progression of NAFLD: P2-HNF4α expression is followed by expression of p-STAT3 which in turn is followed by the expression of c-Myc. Additional larger studies are needed to confirm these findings.
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Affiliation(s)
- Mamoun Younes
- Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA
| | - Lin Zhang
- Departments of Pathology and Laboratory Medicine, McGovern Medical School at the University of Texas Health Science Center (UTHealth), Houston, TX 77225, USA
| | - Baharan Fekry
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UTHealth), Houston, TX 77225, USA
| | - Kristin Eckel-Mahan
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UTHealth), Houston, TX 77225, USA
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14
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Feng Y, Wang P, Cai L, Zhan M, He F, Wang J, Li Y, Gega E, Zhang W, Zhao W, Xin Y, Chen X, Ruan Y, Lu L. 3D-Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma. ADVANCED GENETICS (HOBOKEN, N.J.) 2022; 3:2100010. [PMID: 36911294 PMCID: PMC9993472 DOI: 10.1002/ggn2.202100010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 05/03/2022] [Indexed: 11/10/2022]
Abstract
The fundamental cause of transcription dysregulation in hepatocellular carcinoma (HCC) remains elusive. To investigate the underlying mechanisms, comprehensive 3D-epigenomic analyses are performed in cellular models of THLE2 (a normal hepatocytes cell line) and HepG2 (a hepatocellular carcinoma cell line) using integrative approaches for chromatin topology, genomic and epigenomic variation, and transcriptional output. Comparing the 3D-epigenomes in THLE2 and HepG2 reveal that most HCC-associated genes are organized in complex chromatin interactions mediated by RNA polymerase II (RNAPII). Incorporation of genome-wide association studies (GWAS) data enables the identification of non-coding genetic variants that are enriched in distal enhancers connecting to the promoters of HCC-associated genes via long-range chromatin interactions, highlighting their functional roles. Interestingly, CTCF binding and looping proximal to HCC-associated genes appear to form chromatin architectures that overarch RNAPII-mediated chromatin interactions. It is further demonstrated that epigenetic variants by DNA hypomethylation at a subset of CTCF motifs proximal to HCC-associated genes can modify chromatin topological configuration, which in turn alter RNAPII-mediated chromatin interactions and lead to dysregulation of transcription. Together, the 3D-epigenomic analyses provide novel insights of multifaceted interplays involving genetics, epigenetics, and chromatin topology in HCC cells.
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Affiliation(s)
- Yuliang Feng
- Zhuhai Precision Medical CenterZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiGuangdong519000P. R. China
- The Jackson Laboratory for Genomic MedicineFarmingtonCT06032USA
| | - Ping Wang
- The Jackson Laboratory for Genomic MedicineFarmingtonCT06032USA
| | - Liuyang Cai
- The Jackson Laboratory for Genomic MedicineFarmingtonCT06032USA
| | - Meixiao Zhan
- Zhuhai Precision Medical CenterZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiGuangdong519000P. R. China
| | - Fan He
- Department of Interventional RadiologyShenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenGuangdong518020P. R. China
| | - Jiahui Wang
- The Jackson Laboratory for Genomic MedicineFarmingtonCT06032USA
| | - Yong Li
- Zhuhai Precision Medical CenterZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiGuangdong519000P. R. China
| | - Eva Gega
- The Jackson Laboratory for Genomic MedicineFarmingtonCT06032USA
| | - Wei Zhang
- Department of Interventional RadiologyShenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenGuangdong518020P. R. China
| | - Wei Zhao
- Zhuhai Precision Medical CenterZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiGuangdong519000P. R. China
| | - Yongjie Xin
- Zhuhai Precision Medical CenterZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiGuangdong519000P. R. China
| | - Xudong Chen
- Department of Interventional RadiologyShenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology)ShenzhenGuangdong518020P. R. China
| | - Yijun Ruan
- The Jackson Laboratory for Genomic MedicineFarmingtonCT06032USA
| | - Ligong Lu
- Zhuhai Precision Medical CenterZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiGuangdong519000P. R. China
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15
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Roh YJ, Kim Y, Lee JS, Oh JH, Lee SM, Yoon EL, Lee SR, Jun DW. Regulation of Hepatocyte Nuclear Factor 4α Attenuated Lipotoxicity but Increased Bile Acid Toxicity in Non-Alcoholic Fatty Liver Disease. LIFE (BASEL, SWITZERLAND) 2022; 12:life12111682. [PMID: 36362837 PMCID: PMC9699296 DOI: 10.3390/life12111682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/14/2022] [Accepted: 10/19/2022] [Indexed: 12/03/2022]
Abstract
Hepatocyte nuclear factor 4 alpha (HNF4α) is a key master transcriptional factor for hepatic fat and bile acid metabolic pathways. We aimed to investigate the role of HNF4α in non-alcoholic fatty liver disease (NAFLD). The role of HNF4α was evaluated in free fatty acid-induced lipotoxicity and chenodeoxycholic acid (CDCA)-induced bile acid toxicity. Furthermore, the role of HNF4α was evaluated in a methionine choline deficiency (MCD)-diet-induced NAFLD model. The overexpression of HNF4α reduced intracellular lipid contents and attenuated palmitic acid (PA)-induced lipotoxicity. However, the protective effects of HNF4α were reversed when CDCA was used in a co-treatment with PA. HNF4α knockdown recovered cell death from bile acid toxicity. The inhibition of HNF4α decreased intrahepatic inflammation and the NAFLD activity score in the MCD model. Hepatic HNF4α inhibition can attenuate bile acid toxicity and be more effective as a therapeutic strategy in NAFLD patients; however, it is necessary to study the optimal timing of HNF4α inhibition.
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Affiliation(s)
- Yoon Jin Roh
- Department of Dermatology, Chung-Ang University Hospital, Seoul 04763, Korea
| | - Yun Kim
- Hanyang Medicine-Engineering-Bio Collaborative & Comprehensive Center for Drug Development, Hanyang University, Seoul 04763, Korea
- College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Korea
| | - Jae Sun Lee
- Department of Translational Medical Science, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul 04763, Korea
| | - Ju Hee Oh
- Department of Translational Medical Science, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul 04763, Korea
| | - Seung Min Lee
- Department of Translational Medical Science, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul 04763, Korea
| | - Eileen Laurel Yoon
- Department of Gastroenterology, Hanyang University School of Medicine, Seoul 04763, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Korea
| | - Sung Ryol Lee
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Korea
- Correspondence: (S.R.L.); (D.W.J.)
| | - Dae Won Jun
- Hanyang Medicine-Engineering-Bio Collaborative & Comprehensive Center for Drug Development, Hanyang University, Seoul 04763, Korea
- Department of Translational Medical Science, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul 04763, Korea
- Department of Gastroenterology, Hanyang University School of Medicine, Seoul 04763, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Korea
- Correspondence: (S.R.L.); (D.W.J.)
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16
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Puppala S, Spradling-Reeves KD, Chan J, Birnbaum S, Newman DE, Comuzzie AG, Mahaney MC, VandeBerg JL, Olivier M, Cox LA. Hepatic transcript signatures predict atherosclerotic lesion burden prior to a 2-year high cholesterol, high fat diet challenge. PLoS One 2022; 17:e0271514. [PMID: 35925965 PMCID: PMC9352111 DOI: 10.1371/journal.pone.0271514] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 07/04/2022] [Indexed: 11/19/2022] Open
Abstract
The purpose of this study was to identify molecular mechanisms by which the liver influences total lesion burden in a nonhuman primate model (NHP) of cardiovascular disease with acute and chronic feeding of a high cholesterol, high fat (HCHF) diet. Baboons (47 females, 64 males) were fed a HCHF diet for 2 years (y); liver biopsies were collected at baseline, 7 weeks (w) and 2y, and lesions were quantified in aortic arch, descending aorta, and common iliac at 2y. Unbiased weighted gene co-expression network analysis (WGCNA) revealed several modules of hepatic genes correlated with lesions at different time points of dietary challenge. Pathway and network analyses were performed to study the roles of hepatic module genes. More significant pathways were observed in males than females. In males, we found modules enriched for genes in oxidative phosphorylation at baseline, opioid signaling at 7w, and EIF2 signaling and HNF1A and HNF4A networks at baseline and 2y. One module enriched for fatty acid β oxidation pathway genes was found in males and females at 2y. To our knowledge, this is the first study of a large NHP cohort to identify hepatic genes that correlate with lesion burden. Correlations of baseline and 7w module genes with lesions at 2y were observed in males but not in females. Pathway analyses of baseline and 7w module genes indicate EIF2 signaling, oxidative phosphorylation, and μ-opioid signaling are possible mechanisms that predict lesion formation induced by HCHF diet consumption in males. Our findings of coordinated hepatic transcriptional response in male baboons but not female baboons indicate underlying molecular mechanisms differ between female and male primate atherosclerosis.
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Affiliation(s)
- Sobha Puppala
- Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Kimberly D. Spradling-Reeves
- Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Jeannie Chan
- Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Shifra Birnbaum
- Texas Biomedical Research Institute, San Antonio, Texas, United States of America
| | - Deborah E. Newman
- Texas Biomedical Research Institute, San Antonio, Texas, United States of America
| | | | - Michael C. Mahaney
- South Texas Diabetes and Obesity Institute and Department of Human Genetics, The University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas, United States of America
| | - John L. VandeBerg
- South Texas Diabetes and Obesity Institute and Department of Human Genetics, The University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas, United States of America
| | - Michael Olivier
- Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Laura A. Cox
- Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
- Texas Biomedical Research Institute, San Antonio, Texas, United States of America
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17
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Gunewardena S, Huck I, Walesky C, Robarts D, Weinman S, Apte U. Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans. Hepatology 2022; 76:372-386. [PMID: 35006629 PMCID: PMC9762158 DOI: 10.1002/hep.32326] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Hepatocyte nuclear factor 4 alpha (HNF4α) is indispensable for hepatocyte differentiation and critical for maintaining liver health. Here, we demonstrate that loss of HNF4α activity is a crucial step in the pathogenesis of chronic liver diseases (CLDs) that lead to development of HCC. APPROACH AND RESULTS We developed an HNF4α target gene signature, which can accurately determine HNF4α activity, and performed an exhaustive in silico analysis using hierarchical and K-means clustering, survival, and rank-order analysis of 30 independent data sets containing over 3500 individual samples. The association of changes in HNF4α activity to CLD progression of various etiologies, including HCV- and HBV-induced liver cirrhosis (LC), NAFLD/NASH, and HCC, was determined. Results revealed a step-wise reduction in HNF4α activity with each progressive stage of pathogenesis. Cluster analysis of LC gene expression data sets using the HNF4α signature showed that loss of HNF4α activity was associated with progression of Child-Pugh class, faster decompensation, incidence of HCC, and lower survival with and without HCC. A moderate decrease in HNF4α activity was observed in NAFLD from normal liver, but a further significant decline was observed in patients from NAFLD to NASH. In HCC, loss of HNF4α activity was associated with advanced disease, increased inflammatory changes, portal vein thrombosis, and substantially lower survival. CONCLUSIONS In conclusion, these data indicate that loss of HNF4α function is a common event in the pathogenesis of CLDs leading to HCC and is important from both diagnostic and therapeutic standpoints.
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Affiliation(s)
- Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
| | - Ian Huck
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Chad Walesky
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Dakota Robarts
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Steven Weinman
- Department of Medicine, University of Kansas Medical Center, Kansas City, KS
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS
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18
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McLimans CJ, Shelledy K, Conrad W, Prendergast K, Le AN, Grant CJ, Buonaccorsi VP. Potential biomarkers of endocrine and habitat disruption identified via RNA-Seq in Salvelinus fontinalis with proximity to fracking operations in Pennsylvania headwater stream ecosystems. ECOTOXICOLOGY (LONDON, ENGLAND) 2022; 31:1044-1055. [PMID: 35834075 DOI: 10.1007/s10646-022-02564-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/25/2022] [Indexed: 06/15/2023]
Abstract
Unconventional natural gas development (fracking) has been a rapidly expanding technique used for the extraction of natural gas from the Marcellus Shale formation in Pennsylvania. There remains a knowledge gap regarding the ecological impacts of fracking, especially regarding the long-term health of native Brook trout (Salvelinus fontinalis) populations. During the summer of 2015, Brook trout were sampled from twelve streams located in forested, northwestern Pennsylvania in order to evaluate the impacts of fracking on Brook trout. Four stream sites were undisturbed (no fracking activity), three had a developed well pad without fracking activity, and five had active fracking with natural gas production. Liver tissue was isolated from two to five fish per stream and underwent RNA-Seq analysis to identify differentially expressed genes between ecosystems with differing fracking status. Data were analyzed individually and with samples pooled within-stream to account for hierarchical data structure and variation in sample coverage within streams. Differentially expressed and differentially alternatively spliced genes had functions related to lipid and steroid metabolism, mRNA processing, RNA polymerase and protein regulation. Unique to our study, genes related to xenobiotic and stress responses were found as well as potential markers for endocrine disruption and saline adaptation that were identified in watersheds with active fracking activity. These results support the utility of RNA-Seq to assess trout health and suggest detrimental impacts of fracking on sensitive trout populations.
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Affiliation(s)
| | | | - William Conrad
- Department of Biology, Juniata College, Huntingdon, PA, USA
| | | | - Anh N Le
- Department of Biology, Juniata College, Huntingdon, PA, USA
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19
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Fatty Hepatocytes Induce Skeletal Muscle Atrophy In Vitro: A New 3D Platform to Study the Protective Effect of Albumin in Non-Alcoholic Fatty Liver. Biomedicines 2022; 10:biomedicines10050958. [PMID: 35625696 PMCID: PMC9139027 DOI: 10.3390/biomedicines10050958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 02/04/2023] Open
Abstract
The liver neutralizes endogenous and exogenous toxins and metabolites, being metabolically interconnected with many organs. Numerous clinical and experimental studies show a strong association between Non-alcoholic fatty liver disease (NAFLD) and loss of skeletal muscle mass known as sarcopenia. Liver transplantation solves the hepatic-related insufficiencies, but it is unable to revert sarcopenia. Knowing the mechanism(s) by which different organs communicate with each other is crucial to improve the drug development that still relies on the two-dimensional models. However, those models fail to mimic the pathological features of the disease. Here, both liver and skeletal muscle cells were encapsulated in gelatin methacryloyl and carboxymethylcellulose to recreate the disease’s phenotype in vitro. The 3D hepatocytes were challenged with non-esterified fatty acids (NEFAs) inducing features of Non-alcoholic fatty liver (NAFL) such as lipid accumulation, metabolic activity impairment and apoptosis. The 3D skeletal muscle tissues incubated with supernatant from fatty hepatocytes displayed loss of maturation and atrophy. This study demonstrates the connection between the liver and the skeletal muscle in NAFL, narrowing down the players for potential treatments. The tool herein presented was employed as a customizable 3D in vitro platform to assess the protective effect of albumin on both hepatocytes and myotubes.
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20
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Li HY, Peng ZG. Targeting lipophagy as a potential therapeutic strategy for nonalcoholic fatty liver disease. Biochem Pharmacol 2022; 197:114933. [PMID: 35093393 DOI: 10.1016/j.bcp.2022.114933] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/04/2022] [Accepted: 01/21/2022] [Indexed: 02/09/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming an increasingly serious disease worldwide. Unfortunately, no specific drug has been approved to treat NAFLD. Accumulating evidence suggests that lipotoxicity, which is induced by an excess of intracellular triacylglycerols (TAGs), is a potential mechanism underlying the ill-defined progression of NAFLD. Under physiological conditions, a balance is maintained between TAGs and free fatty acids (FFAs) in the liver. TAGs are catabolized to FFAs through neutral lipolysis and/or lipophagy, while FFAs can be anabolized to TAGs through an esterification reaction. However, in the livers of patients with NAFLD, lipophagy appears to fail. Reversing this abnormal state through several lipophagic molecules (mTORC1, AMPK, PLIN, etc.) facilitates NAFLD amelioration; therefore, restoring failed lipophagy may be a highly efficient therapeutic strategy for NAFLD. Here, we outline the lipophagy phases with the relevant important proteins and discuss the roles of lipophagy in the progression of NAFLD. Additionally, the potential candidate drugs with therapeutic value targeting these proteins are discussed to show novel strategies for future treatment of NAFLD.
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Affiliation(s)
- Hong-Ying Li
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Zong-Gen Peng
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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21
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HNF4A Regulates the Proliferation and Tumor Formation of Cervical Cancer Cells through the Wnt/β-Catenin Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8168988. [PMID: 35132353 PMCID: PMC8817108 DOI: 10.1155/2022/8168988] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 12/22/2021] [Indexed: 12/25/2022]
Abstract
Hepatocyte nuclear factor 4 alpha (HNF4A) is a transcriptional factor which plays an important role in the development of the liver, kidney, and intestines. Nevertheless, its role in cervical cancer and the underlying mechanism remain unknown. In this study, both immunohistochemistry and western blotting revealed that the expression of HNF4A was downregulated in cervical cancer. Xenograft assays suggested that HN4A could inhibit tumorigenic potential of cervical cancer in vivo. Functional studies illustrated that HNF4A also inhibited the proliferation and viability of cervical cancer cells in vitro. In addition, FACS analysis implied that HNF4A could induce cell cycle arrest from the G0/G1 phase to S phase. Further studies suggested that HNF4A downregulated the activity of the Wnt/β-catenin pathway. Altogether, our data demonstrated that HNF4A inhibited tumor formation and proliferation of cervical cancer cells through suppressing the activity of the Wnt/β-catenin pathway.
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22
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Identification of a 17-gene-signature in Non-alcoholic Steatohepatitis and Its Relationship with Immune Cell Infiltration. HEPATITIS MONTHLY 2021. [DOI: 10.5812/hepatmon.116366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Non-alcoholic steatohepatitis (NASH) is a risk factor for hepatocellular carcinoma, but the understanding of the regulatory mechanisms driving NASH is not comprehensive. Objectives: We aimed to identify the potential markers of NASH and explore their relationship with immune cell populations. Methods: Five gene expression datasets for NASH were downloaded from the Gene Expression Omnibus and European Bioinformatics Institute Array Express databases. Differentially expressed genes (DEGs) between NASH and controls were screened. Gene Ontology-Biological Process (GO-BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed for functional enrichment analysis of DEGs. Among the candidate genes selected from the protein-protein interaction (PPI) network and module analysis, DEG signatures were further identified using least absolute shrinkage and selection operator regression analysis. The Spearman correlation coefficient was calculated to assess the correlation between DEG signatures and immune cell abundance based on the CIBERSORT algorithm. Results: We screened 403 upregulated, and 158 downregulated DEGs for NASH, and they were mainly enriched in GO-BP, including the inflammatory response, innate immune response, signal transduction, and KEGG pathways, such as the pathways involved in cancer (e.g., the PI3K-Akt signaling pathway), and focal adhesion. We then screened 73 candidate genes from the PPI network and module analysis and finally identified 17 DEG signatures. By evaluating their relationship with immune cell populations, 12 DEG signatures were found to correlate with activated dendritic cells, resting dendritic cells, M2 macrophages, monocytes, neutrophils, and resting memory CD4 T cells, which were significantly different between the NASH and control tissues. Conclusions: We identified a 17-DEG-signature as a candidate biomarker for NASH and analyzed its relationship with immune infiltration in NASH.
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23
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Pan G, Cavalli M, Wadelius C. Polymorphisms rs55710213 and rs56334587 regulate SCD1 expression by modulating HNF4A binding. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2021; 1864:194724. [PMID: 34171462 DOI: 10.1016/j.bbagrm.2021.194724] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 02/07/2023]
Abstract
The stearoyl-CoA desaturase 1 (SCD1) gene at 10q24.31 encodes the rate limiting enzyme SCD1 that catalyzes the biosynthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids (SFAs). Dysregulated SCD1 activity has been observed in many human diseases including non-alcoholic fatty liver disease (NAFLD), obesity, hypertension, hyperlipidemia, metabolic syndrome and several types of cancer. HNF4A is a central regulator of glucose and lipid metabolism and previous studies suggested that it is deeply involved in regulating the SCD1 activity in the liver. However, the underlying mechanisms on whether and how SCD1 is regulated by HNF4A have not been explored in detail. In this study, we found that HNF4A regulates SCD1 expression by directly binding to the key regulatory regions in the SCD1 locus. Knocking down of HNF4A significantly downregulated the expression of SCD1. Variants rs55710213 and rs56334587 in intron 5 of SCD1 directly reside in a canonical HNF4A binding site. The GG haplotype of rs55710213 and rs56334587 is associated with decreased SCD1 activity by disrupting the binding of HNF4A, which further decreased the enhancer activity and SCD1 expression. In conclusion, our study demonstrated that SCD1 is directly regulated by HNF4A, which may be helpful in the understanding of the altered metabolic pathways in many diseases associated with dysregulated SCD1 or HNF4A or both.
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Affiliation(s)
- Gang Pan
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
| | - Marco Cavalli
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Claes Wadelius
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
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24
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Huck I, Morris EM, Thyfault J, Apte U. Hepatocyte-Specific Hepatocyte Nuclear Factor 4 Alpha (HNF4) Deletion Decreases Resting Energy Expenditure by Disrupting Lipid and Carbohydrate Homeostasis. Gene Expr 2021; 20:157-168. [PMID: 33691903 PMCID: PMC8201658 DOI: 10.3727/105221621x16153933463538] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Hepatocyte nuclear factor 4 alpha (HNF4) is required for hepatocyte differentiation and regulates expression of genes involved in lipid and carbohydrate metabolism including those that control VLDL secretion and gluconeogenesis. Whereas previous studies have focused on specific genes regulated by HNF4 in metabolism, its overall role in whole-body energy utilization has not been studied. In this study, we used indirect calorimetry to determine the effect of hepatocyte-specific HNF4 deletion (HNF4-KO) in mice on whole-body energy expenditure (EE) and substrate utilization in fed, fasted, and high-fat diet (HFD) conditions. HNF4-KO had reduced resting EE during fed conditions and higher rates of carbohydrate oxidation with fasting. HNF4-KO mice exhibited decreased body mass caused by fat mass depletion despite no change in energy intake and evidence of positive energy balance. HNF4-KO mice were able to upregulate lipid oxidation during HFD, suggesting that their metabolic flexibility was intact. However, only hepatocyte-specific HNF4-KO mice exhibited significant reduction in basal metabolic rate and spontaneous activity during HFD. Consistent with previous studies, hepatic gene expression in HNF4-KO supports decreased gluconeogenesis and decreased VLDL export and hepatic -oxidation in HNF4-KO livers across all feeding conditions. Together, our data suggest that deletion of hepatic HNF4 increases dependence on dietary carbohydrates and endogenous lipids for energy during fed and fasted conditions by inhibiting hepatic gluconeogenesis, hepatic lipid export, and intestinal lipid absorption resulting in decreased whole-body energy expenditure. These data clarify the role of hepatic HNF4 on systemic metabolism and energy homeostasis.
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Affiliation(s)
- Ian Huck
- *Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - E. Matthew Morris
- †Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
| | - John Thyfault
- †Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
- ‡Research Service, Kansas City VA Medical Center, Kansas City, KS, USA
| | - Udayan Apte
- *Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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25
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Pirfenidone modifies hepatic miRNAs expression in a model of MAFLD/NASH. Sci Rep 2021; 11:11709. [PMID: 34083664 PMCID: PMC8175718 DOI: 10.1038/s41598-021-91187-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/24/2021] [Indexed: 12/18/2022] Open
Abstract
miRNAs are involved in the development of metabolic associated fatty liver disease (MAFLD) and nonalcoholic steatohepatitis (NASH). We aimed to evaluate modifications by prolonged-release pirfenidone (PR-PFD) on key hepatic miRNAs expression in a MAFLD/NASH model. First, male C57BL/6J mice were randomly assigned into groups and fed with conventional diet (CVD) or high fat and carbohydrate diet (HFD) for 16 weeks. At the end of the eighth week, HFD mice were divided in two and only one half was treated with 300 mg/kg/day of PR-PFD mixed with food. Hepatic expression of miRNAs and target genes that participate in inflammation and lipid metabolism was determined by qRT-PCR and transcriptome by microarrays. Increased hepatic expression of miR-21a-5p, miR-34a-5p, miR-122-5p and miR-103-3p in MAFLD/NASH animals was reduced with PR-PFD. Transcriptome analysis showed that 52 genes involved in lipid and collagen biosynthesis and inflammatory response were downregulated in PR-PFD group. The expression of Il1b, Tnfa, Il6, Tgfb1, Col1a1, and Srebf1 were decreased in PR-PFD treated animals. MAFLD/NASH animals compared to CVD group showed modifications in gene metabolic pathways implicated in lipid metabolic process, inflammatory response and insulin resistance; PR-PFD reversed these modifications.
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26
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Lu D, Xia Q, Yang Z, Gao S, Sun S, Luo X, Li Z, Zhang X, Han S, Li X, Cao M. ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevation of GPX4 expression and lipid accumulation. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:661. [PMID: 33987359 PMCID: PMC8106050 DOI: 10.21037/atm-21-471] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background ENO3 expression is upregulated in Non-alcoholic fatty liver disease (NAFLD) patient tissues, demonstrated that ENO3 might play crucial roles in NAFLD. However, the mechanism of ENO3 in NAFLD remains unclear. Therefore, this study aimed to investigate the regulatory mechanism of ENO3 in the progression of non-alcoholic steatohepatitis (NASH) in vivo and vitro NASH model. Methods In vivo and vitro NASH model were established by methionine-choline deficient (MCD)-diet feeding and high free fatty acid (HFFA) induction in L02 cells. Loss and gain function of ENO3 and GPX4 was performed to study the mechanism in NASH. Western blot was used to detect the expression of ENO3 and GPX4. Hematoxylin and eosin (H&E), picrosirius Red and Oil Red O staining was used to evaluate histopathology of liver in NASH model. Ferroptosis indicators were measured by assay kits according to the manufacturer's instructions. Results NASH mouse model was successfully established induced by MCD diet with steatosis, inflammatory infiltration, ballooning and fibrosis observed in the liver tissue. The expression of ENO3 and GPX4 was significantly elevated while ferroptosis was inhibited in NASH mice and cell model. Upregulation of both ENO3 and GPX4 could promote the lipid accumulation in L02 cells. In addition, overexpressed ENO3 attenuated the status of ferroptosis. Conclusions In the present study, we demonstrate that ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevating GPX4 expression and lipid accumulation. These findings provided solid foundation for the mechanism of ferroptosis on the progression of NASH regulated by ENO3, suggesting that ENO3 may be a potential therapeutic target for NASH.
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Affiliation(s)
- Di Lu
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Qiaoyun Xia
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Zhiyu Yang
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Shanjun Gao
- Microbiome Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Suofeng Sun
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Xiaoying Luo
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Zhen Li
- Microbiome Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiulei Zhang
- Microbiome Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuangyin Han
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Xiuling Li
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Mingbo Cao
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
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27
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Khan N, Laudermilk L, Ware J, Rosa T, Mathews K, Gay E, Amato G, Maitra R. Peripherally Selective CB1 Receptor Antagonist Improves Symptoms of Metabolic Syndrome in Mice. ACS Pharmacol Transl Sci 2021; 4:757-764. [PMID: 33860199 DOI: 10.1021/acsptsci.0c00213] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Indexed: 12/11/2022]
Abstract
Metabolic syndrome (MetS) is a complex disorder that stems from the additive effects of multiple underlying causes such as obesity, insulin resistance, and chronic low-grade inflammation. The endocannabinoid system plays a central role in appetite regulation, energy balance, lipid metabolism, insulin sensitivity, and β-cell function. The type 1 cannabinoid receptor (CB1R) antagonist SR141716A (rimonabant) showed promising antiobesity effects, but its use was discontinued due to adverse psychiatric events in some users. These adverse effects are due to antagonism of CB1R in the central nervous system (CNS). As such, CNS-sparing CB1R antagonists are presently being developed for various indications. In this study, we report that a recently described compound, 3-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}-1-[6-(difluoromethoxy)pyridin-3-yl]urea (RTI1092769), a pyrazole based weak inverse agonist/antagonist of CB1 with very limited brain exposure, improves MetS related complications. Treatment with RTI1092769 inhibited weight gain and improved glucose utilization in obese mice maintained on a high fat diet. Hepatic triglyceride content and steatosis significantly improved with treatment. These phenotypes were supported by improvement in several biomarkers associated with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). These results reinforce the idea that CB1 antagonists with limited brain exposure should be pursued for MetS and other important indications.
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Affiliation(s)
- Nayaab Khan
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
| | - Lucas Laudermilk
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
| | - Jalen Ware
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
| | - Taylor Rosa
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
| | - Kelly Mathews
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
| | - Elaine Gay
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
| | - George Amato
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
| | - Rangan Maitra
- Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States
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28
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Farinella R, Erbi I, Bedini A, Donato S, Gentiluomo M, Angelucci C, Lupetti A, Cuttano A, Moscuzza F, Tuoni C, Rizzato C, Ciantelli M, Campa D. Polymorphic variants in Sweet and Umami taste receptor genes and birthweight. Sci Rep 2021; 11:4971. [PMID: 33654187 PMCID: PMC7925569 DOI: 10.1038/s41598-021-84491-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/29/2020] [Indexed: 11/25/2022] Open
Abstract
The first thousand days of life from conception have a significant impact on the health status with short, and long-term effects. Among several anthropometric and maternal lifestyle parameters birth weight plays a crucial role on the growth and neurological development of infants. Recent genome wide association studies (GWAS) have demonstrated a robust foetal and maternal genetic background of birth weight, however only a small proportion of the genetic hereditability has been already identified. Considering the extensive number of phenotypes on which they are involved, we focused on identifying the possible effect of genetic variants belonging to taste receptor genes and birthweight. In the human genome there are two taste receptors family the bitter receptors (TAS2Rs) and the sweet and umami receptors (TAS1Rs). In particular sweet perception is due to a heterodimeric receptor encoded by the TAS1R2 and the TAS1R3 gene, while the umami taste receptor is encoded by the TAS1R1 and the TAS1R3 genes. We observed that carriers of the T allele of the TAS1R1-rs4908932 SNPs showed an increase in birthweight compared to GG homozygotes Coeff: 87.40 (35.13-139.68) p-value = 0.001. The association remained significant after correction for multiple testing. TAS1R1-rs4908932 is a potentially functional SNP and is in linkage disequilibrium with another polymorphism that has been associated with BMI in adults showing the importance of this variant from the early stages of conception through all the adult life.
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Affiliation(s)
| | - Ilaria Erbi
- Department of Biology, University of Pisa, Pisa, Italy
| | - Alice Bedini
- Division of Neonatology, Santa Chiara Hospital, Via Roma, 67, 56126, Pisa, Italy
| | - Sara Donato
- Department of Biology, University of Pisa, Pisa, Italy
| | | | - Claudia Angelucci
- Division of Neonatology, Santa Chiara Hospital, Via Roma, 67, 56126, Pisa, Italy
| | - Antonella Lupetti
- Department of Translation Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Armando Cuttano
- Division of Neonatology, Santa Chiara Hospital, Via Roma, 67, 56126, Pisa, Italy
| | - Francesca Moscuzza
- Division of Neonatology, Santa Chiara Hospital, Via Roma, 67, 56126, Pisa, Italy
| | - Cristina Tuoni
- Division of Neonatology, Santa Chiara Hospital, Via Roma, 67, 56126, Pisa, Italy
| | - Cosmeri Rizzato
- Department of Translation Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | | | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy
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29
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Zhan X, Zhao A. Transcription factor FOXA3 promotes the development of Hepatoblastoma via regulating HNF1A, AFP, and ZFHX3 expression. J Clin Lab Anal 2020; 35:e23686. [PMID: 33368532 PMCID: PMC7957975 DOI: 10.1002/jcla.23686] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/19/2020] [Accepted: 12/01/2020] [Indexed: 12/15/2022] Open
Abstract
Objective In this research paper, we aimed to study the role of FOXA3 in hepatoblastoma (HB) and the molecular mechanism. Methods Immunohistochemistry was applied to determine the expression situation of FOXA3 and AFP in HB tissues and the adjacent normal tissues. FOXA3, HNF1A, and ZFHX3 expressions in HB tissues and the normal tissues were measured by Western blot. HB cell lines were randomly divided into 4 groups: Model, si‐NC, si‐FOXA3‐1, and si‐FOXA3‐2 group. The HB cell viability and colony formation characteristics in the 4 groups were explored by CCK‐8 and cell cloning formation assay, respectively. The expression of FOXA3, AFP, HNF1A, ZFHX3, and MYC in HB cells after knockdown of FOXA3 was measured. Results FOXA3, AFP, and HNF1A expressions were significantly up‐regulated in HB tissues, while ZFHX3 expression was down‐regulated. Knockdown of FOXA3 markedly inhibited HB cell viability and cloning formation ability. Knockdown of FOXA3 decreased FOXA3, AFP, and HNF1A/MYC expression, while increased ZFHX3 expression. Conclusion FOXA3 promotes the occurrence and development of HB by up‐regulating AFP and HNF1A/MYC expression, and down‐regulating ZFHX3 expression.
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Affiliation(s)
- Xiaoyun Zhan
- Department of Childhood Hematology, Maternal and Child Hospital of Hubei province, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China
| | - Alan Zhao
- Department of Childhood Hematology, Maternal and Child Hospital of Hubei province, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China
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30
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Kozaczek M, Bottje W, Kong B, Dridi S, Albataineh D, Lassiter K, Hakkak R. Long-Term Soy Protein Isolate Consumption Reduces Liver Steatosis Through Changes in Global Transcriptomics in Obese Zucker Rats. Front Nutr 2020; 7:607970. [PMID: 33363197 PMCID: PMC7759473 DOI: 10.3389/fnut.2020.607970] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022] Open
Abstract
To determine how soy protein isolate (SPI) ameliorated liver steatosis in male obese Zucker rats, we conducted global transcriptomic expression (RNAseq) analysis on liver samples of male rats fed either the SPI or a control casein (CAS)-based diet (n = 8 per group) for 16 weeks. Liver transcriptomics were analyzed using an Ilumina HiSeq system with 2 × 100 base pair paired-end reads method. Bioinformatics was conducted using Ingenuity Pathway Analysis (IPA) software (Qiagen, CA) with P < 0.05 and 1.3-fold differential expression cutoff values. Regression analysis between RNAseq data and targeted mRNA expression analysis of 12 top differentially expressed genes (from the IPA program) using quantitative PCR (qPCR) revealed a significant regression analysis (r2 = 0.69, P = 0.0008). In addition, all qPCR values had qualitatively similar direction of up- or down-regulation compared to the RNAseq transcriptomic data. Diseases and function analyses that were based on differentially expressed target molecules in the dataset predicted that lipid metabolism would be enhanced whereas inflammation was predicted to be inhibited in SPI-fed compared to CAS-fed rats at 16 weeks. Combining upstream regulator and regulator effects functions in IPA facilitates the prediction of upstream regulators (e.g., transcription regulators) that could play important roles in attenuating or promoting liver steatosis due to SPI or CAS diets. Upstream regulators that were predicted to be activated (from expression of down-stream targets) linked to increased conversion of lipid and transport of lipid in SPI-fed rats included hepatocyte nuclear factor 4 alpha (HNF4A) and aryl hydrocarbon receptor (AHR). Upstream regulators that were predicted to be activated in CAS-fed rats linked to activation of phagocytosis and neutrophil chemotaxis included colony stimulating factor 2 and tumor necrosis factor. The results provide clear indication that long-term SPI-fed rats exhibited diminished inflammatory response and increased lipid transport in liver compared to CAS-fed rats that likely would contribute to reduced liver steatosis in this obese Zucker rat model.
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Affiliation(s)
- Melisa Kozaczek
- Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Walter Bottje
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Byungwhi Kong
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Sami Dridi
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Diyana Albataineh
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Kentu Lassiter
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States
| | - Reza Hakkak
- Department of Poultry Science & The Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR, United States.,Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Arkansas Children's Research Institute, Little Rock, AR, United States
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31
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Winters SJ, Scoggins CR, Appiah D, Ghooray DT. The hepatic lipidome and HNF4α and SHBG expression in human liver. Endocr Connect 2020; 9:1009-1018. [PMID: 33064664 PMCID: PMC7576643 DOI: 10.1530/ec-20-0401] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 09/16/2020] [Indexed: 01/14/2023]
Abstract
Low plasma levels of sex hormone-binding globulin (SHBG) are a marker for obesity, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The transcription factor HNF4α is a major determinant of hepatic SHBG expression and thereby serum SHBG levels, and mediates in part the association of low SHBG with hyperinsulinemia and hepatic steatosis. We analyzed the lipidome in human liver specimens from a cohort of patients who underwent hepatic resection as a treatment for cancer, providing insight into hepatic lipids in those without extreme obesity or the clinical diagnosis of NAFLD or non-alcoholic steatohepatitis. Both steatosis and high HOMA-IR were associated with higher levels of saturated and unsaturated FA, other than arachidonic, with the most dramatic rise in 18:1 oleate, consistent with increased stearoyl-CoA desaturase activity. Individuals with low HOMA-IR had low levels of total hepatic fatty acids, while both low and high fatty acid levels characterized the high HOMA-IR group. Both insulin resistance and high levels of hepatic fat were associated with low expression levels of HNF4α and thereby SHBG, but the expression of these genes was also low in the absence of these determinants, implying additional regulatory mechanisms that remain to be determined. The relationship of all FA studied to HNFα and SHBG mRNAs was inverse, and similar to that for total triglyceride concentrations, irrespective of chain length and saturation vs unsaturation.
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Affiliation(s)
- Stephen J Winters
- Division of Endocrinology, Metabolism and Diabetes, University of Louisville, Louisville, Kentucky, USA
- Correspondence should be addressed to S J Winters:
| | - Charles R Scoggins
- Division of Surgical Oncology, University of Louisville, Louisville, Kentucky, USA
| | - Duke Appiah
- Department of Public Health, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Dushan T Ghooray
- Division of Endocrinology, Metabolism and Diabetes, University of Louisville, Louisville, Kentucky, USA
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Dolicka D, Sobolewski C, Gjorgjieva M, Correia de Sousa M, Berthou F, De Vito C, Colin DJ, Bejuy O, Fournier M, Maeder C, Blackshear PJ, Rubbia-Brandt L, Foti M. Tristetraprolin Promotes Hepatic Inflammation and Tumor Initiation but Restrains Cancer Progression to Malignancy. Cell Mol Gastroenterol Hepatol 2020; 11:597-621. [PMID: 32987153 PMCID: PMC7806869 DOI: 10.1016/j.jcmgh.2020.09.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular carcinoma (HCC). METHODS TTP expression was investigated in mouse/human models of hepatic metabolic diseases and cancer. The role of TTP in nonalcoholic steatohepatitis and HCC development was further examined through in vivo/vitro approaches using liver-specific TTP knockout mice and a panel of hepatic cancer cells. RESULTS Our data demonstrate that TTP loss in vivo strongly restrains development of hepatic steatosis and inflammation/fibrosis in mice fed a methionine/choline-deficient diet, as well as HCC development induced by the carcinogen diethylnitrosamine. In contrast, low TTP expression fostered migration and invasion capacities of in vitro transformed hepatic cancer cells likely by unleashing expression of key oncogenes previously associated with these cancerous features. Consistent with these data, TTP was significantly down-regulated in high-grade human HCC, a feature further correlating with poor clinical prognosis. Finally, we uncover hepatocyte nuclear factor 4 alpha and early growth response 1, two key transcription factors lost with hepatocyte dedifferentiation, as key regulators of TTP expression. CONCLUSIONS Although TTP importantly contributes to hepatic inflammation and cancer initiation, its loss with hepatocyte dedifferentiation fosters cancer cells migration and invasion. Loss of TTP may represent a clinically relevant biomarker of high-grade HCC associated with poor prognosis.
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MESH Headings
- Animals
- Carcinogenesis/genetics
- Carcinogenesis/immunology
- Carcinogenesis/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Datasets as Topic
- Diethylnitrosamine/administration & dosage
- Diethylnitrosamine/toxicity
- Down-Regulation
- Female
- Gene Expression Regulation, Neoplastic/immunology
- Hepatocytes
- Humans
- Liver/immunology
- Liver/pathology
- Liver Cirrhosis/genetics
- Liver Cirrhosis/immunology
- Liver Cirrhosis/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Liver Neoplasms, Experimental/chemistry
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/immunology
- Liver Neoplasms, Experimental/pathology
- Male
- Mice
- Non-alcoholic Fatty Liver Disease
- Primary Cell Culture
- Prognosis
- RNA-Seq
- Survival Analysis
- Tristetraprolin/genetics
- Tristetraprolin/metabolism
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Affiliation(s)
- Dobrochna Dolicka
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Cyril Sobolewski
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Monika Gjorgjieva
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Marta Correia de Sousa
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Flavien Berthou
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Claudio De Vito
- Division of Clinical Pathology, University Hospitals, Geneva, Switzerland
| | - Didier J Colin
- Centre for Biomedical Imaging and Preclinical Imaging Platform, University of Geneva, Geneva, Switzerland
| | - Olivia Bejuy
- Centre for Biomedical Imaging and Preclinical Imaging Platform, University of Geneva, Geneva, Switzerland
| | - Margot Fournier
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christine Maeder
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Perry J Blackshear
- Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | | | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Translational Research Centre in Onco-haematology, Faculty of Medicine, University of Geneva, Switzerland.
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33
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Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease. Metabolites 2020; 10:metabo10070283. [PMID: 32660130 PMCID: PMC7408131 DOI: 10.3390/metabo10070283] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is the primary risk factor for the pathogenesis of non-alcoholic fatty liver disease (NAFLD), the worldwide prevalence of which continues to increase dramatically. The liver plays a pivotal role in the maintenance of whole-body lipid and glucose homeostasis. This is mainly mediated by the transcriptional activation of hepatic pathways that promote glucose and lipid production or utilization in response to the nutritional state of the body. However, in the setting of chronic excessive nutrition, the dysregulation of hepatic transcriptional machinery promotes lipid accumulation, inflammation, metabolic stress, and fibrosis, which culminate in NAFLD. In this review, we provide our current understanding of the transcription factors that have been linked to the pathogenesis and progression of NAFLD. Using publicly available transcriptomic data, we outline the altered activity of transcription factors among humans with NAFLD. By expanding this analysis to common experimental mouse models of NAFLD, we outline the relevance of mouse models to the human pathophysiology at the transcriptional level.
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34
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He X, Qi Z, Hou H, Gao J, Zhang XX. Effects of chronic cadmium exposure at food limitation-relevant levels on energy metabolism in mice. JOURNAL OF HAZARDOUS MATERIALS 2020; 388:121791. [PMID: 31818666 DOI: 10.1016/j.jhazmat.2019.121791] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 11/25/2019] [Accepted: 11/29/2019] [Indexed: 06/10/2023]
Abstract
Cadmium (Cd) exposure has been implicated in the perturbation of energy metabolism and the development of cardiometabolic disease, but disease predisposition from chronic low-dose Cd exposure remains unclear. This study employed a mouse model to investigate the toxic effects of chronic Cd exposure at food limitation-relevant levels on energy metabolism and the associated liver and gut microbiome functions. Results showed that the Cd exposure induced the perturbation of energy metabolism in mice, evidenced by the alteration of various metabolites associated with the phosphorogen (adenosine triphosphate-creatine phosphate) system, tricarboxylic acid cycle, and lipid metabolism, as well as the increase of the cardiometabolic risk factor, triglyceride. Moreover, both liver and gut microbiome underwent marked structural/histological and functional alterations, prone to the onset of cardiometabolic disease following the Cd exposure. Certain hepatic transcription factors and gut microbes, specifically PPARα, SREBP1c, HNF4A and the Clostridiales_vadinBB60_group, were identified to be highly correlated with altered urinary metabolites, revealing potential toxicological interactions between the liver and gut microbiome, and energy metabolism. Our findings provide new insights into the progression of metabolic diseases induced by Cd exposure. We also propose a stricter Cd limitation in future food safety standards.
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Affiliation(s)
- Xiwei He
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Zhaodong Qi
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Hui Hou
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Jie Gao
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Xu-Xiang Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China.
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Sahoo S, Singh D, Chakraborty P, Jolly MK. Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD. J Clin Med 2020; 9:E870. [PMID: 32235813 PMCID: PMC7141525 DOI: 10.3390/jcm9030870] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/15/2020] [Accepted: 03/18/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in adults and children. It is characterized by excessive accumulation of lipids in the hepatocytes of patients without any excess alcohol intake. With a global presence of 24% and limited therapeutic options, the disease burden of NAFLD is increasing. Thus, it becomes imperative to attempt to understand the dynamics of disease progression at a systems-level. Here, we decoded the emergent dynamics of underlying gene regulatory networks that were identified to drive the initiation and the progression of NAFLD. We developed a mathematical model to elucidate the dynamics of the HNF4α-PPARγ gene regulatory network. Our simulations reveal that this network can enable multiple co-existing phenotypes under certain biological conditions: an adipocyte, a hepatocyte, and a "hybrid" adipocyte-like state of the hepatocyte. These phenotypes may also switch among each other, thus enabling phenotypic plasticity and consequently leading to simultaneous deregulation of the levels of molecules that maintain a hepatic identity and/or facilitate a partial or complete acquisition of adipocytic traits. These predicted trends are supported by the analysis of clinical data, further substantiating the putative role of phenotypic plasticity in driving NAFLD. Our results unravel how the emergent dynamics of underlying regulatory networks can promote phenotypic plasticity, thereby propelling the clinically observed changes in gene expression often associated with NAFLD.
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Affiliation(s)
- Sarthak Sahoo
- Undergraduate Programme, Indian Institute of Science, Bangalore 560012, India
| | - Divyoj Singh
- Undergraduate Programme, Indian Institute of Science, Bangalore 560012, India
| | - Priyanka Chakraborty
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
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Zhang H, Shen Z, Lin Y, Zhang J, Zhang Y, Liu P, Zeng H, Yu M, Chen X, Ning L, Mao X, Cen L, Yu C, Xu C. Vitamin D receptor targets hepatocyte nuclear factor 4α and mediates protective effects of vitamin D in nonalcoholic fatty liver disease. J Biol Chem 2020; 295:3891-3905. [PMID: 32051143 PMCID: PMC7086018 DOI: 10.1074/jbc.ra119.011487] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/07/2020] [Indexed: 02/06/2023] Open
Abstract
Epidemiological studies have suggested a link between vitamin D deficiency and increased risk for nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms have remained unclear. Here, using both clinical samples and experimental rodent models along with several biochemical approaches, we explored the specific effects and mechanisms of vitamin D deficiency in NAFLD pathology. Serum vitamin D levels were significantly lower in individuals with NAFLD and in high-fat diet (HFD)-fed mice than in healthy controls and chow-fed mice, respectively. Vitamin D supplementation ameliorated HFD-induced hepatic steatosis and insulin resistance in mice. Hepatic expression of vitamin D receptor (VDR) was up-regulated in three models of NAFLD, including HFD-fed mice, methionine/choline-deficient diet (MCD)-fed mice, and genetically obese (ob/ob) mice. Liver-specific VDR deletion significantly exacerbated HFD- or MCD-induced hepatic steatosis and insulin resistance and also diminished the protective effect of vitamin D supplementation on NAFLD. Mechanistic experiments revealed that VDR interacted with hepatocyte nuclear factor 4 α (HNF4α) and that overexpression of HNF4α improved HFD-induced NAFLD and metabolic abnormalities in liver-specific VDR-knockout mice. These results suggest that vitamin D ameliorates NAFLD and metabolic abnormalities by activating hepatic VDR, leading to its interaction with HNF4α. Our findings highlight a potential value of using vitamin D for preventing and managing NAFLD by targeting VDR.
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Affiliation(s)
- Hong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Zhe Shen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yiming Lin
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jie Zhang
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yuwei Zhang
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Peihao Liu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Hang Zeng
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Mengli Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xueyang Chen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Longgui Ning
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xinli Mao
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, Linhai 317000, China
| | - Li Cen
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Chengfu Xu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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37
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Moroldo M, Munyaka PM, Lecardonnel J, Lemonnier G, Venturi E, Chevaleyre C, Oswald IP, Estellé J, Rogel-Gaillard C. Integrative analysis of blood and gut microbiota data suggests a non-alcoholic fatty liver disease (NAFLD)-related disorder in French SLA dd minipigs. Sci Rep 2020; 10:234. [PMID: 31937803 PMCID: PMC6959234 DOI: 10.1038/s41598-019-57127-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 12/18/2019] [Indexed: 11/29/2022] Open
Abstract
Minipigs are a group of small-sized swine lines, which show a broad range of phenotype variation and which often tend to be obese. The SLAdd (DD) minipig line was created by the NIH and selected as homozygous at the SLA locus. It was brought to France more than 30 years ago and maintained inbred ever since. In this report, we characterized the physiological status of a herd of French DD pigs by measuring intermediate phenotypes from blood and faeces and by using Large White (LW) pigs as controls. Three datasets were produced, i.e. complete blood counts (CBCs), microarray-based blood transcriptome, and faecal microbiota obtained by 16S rRNA sequencing. CBCs and expression profiles suggested a non-alcoholic fatty liver disease (NAFLD)-related pathology associated to comorbid cardiac diseases. The characterization of 16S sequencing data was less straightforward, suggesting only a potential weak link to obesity. The integration of the datasets identified several fine-scale associations between CBCs, gene expression, and faecal microbiota composition. NAFLD is a common cause of chronic liver disease in Western countries and is linked to obesity, type 2 diabetes mellitus and cardiac pathologies. Here we show that the French DD herd is potentially affected by this syndrome.
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Affiliation(s)
- Marco Moroldo
- Université Paris Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France.
| | - Peris Mumbi Munyaka
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada
| | - Jérôme Lecardonnel
- Université Paris Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Gaëtan Lemonnier
- Université Paris Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | | | | | - Isabelle P Oswald
- Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toxalim, 31027, Toulouse, France
| | - Jordi Estellé
- Université Paris Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
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Ye J, Lin Y, Wang Q, Li Y, Zhao Y, Chen L, Wu Q, Xu C, Zhou C, Sun Y, Ye W, Bai F, Zhou T. Integrated Multichip Analysis Identifies Potential Key Genes in the Pathogenesis of Nonalcoholic Steatohepatitis. Front Endocrinol (Lausanne) 2020; 11:601745. [PMID: 33324350 PMCID: PMC7726207 DOI: 10.3389/fendo.2020.601745] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/30/2020] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) is rapidly becoming a major chronic liver disease worldwide. However, little is known concerning the pathogenesis and progression mechanism of NASH. Our aim here is to identify key genes and elucidate their biological function in the progression from hepatic steatosis to NASH. METHODS Gene expression datasets containing NASH patients, hepatic steatosis patients, and healthy subjects were downloaded from the Gene Expression Omnibus database, using the R packages biobase and GEOquery. Differentially expressed genes (DEGs) were identified using the R limma package. Functional annotation and enrichment analysis of DEGs were undertaken using the R package ClusterProfile. Protein-protein interaction (PPI) networks were constructed using the STRING database. RESULTS Three microarray datasets GSE48452, GSE63067 and GSE89632 were selected. They included 45 NASH patients, 31 hepatic steatosis patients, and 43 healthy subjects. Two up-regulated and 24 down-regulated DEGs were found in both NASH patients vs. healthy controls and in steatosis subjects vs. healthy controls. The most significantly differentially expressed genes were FOSB (P = 3.43×10-15), followed by CYP7A1 (P = 2.87×10-11), and FOS (P = 6.26×10-11). Proximal promoter DNA-binding transcription activator activity, RNA polymerase II-specific (P = 1.30×10-5) was the most significantly enriched functional term in the gene ontology analysis. KEGG pathway enrichment analysis indicated that the MAPK signaling pathway (P = 3.11×10-4) was significantly enriched. CONCLUSION This study characterized hub genes of the liver transcriptome, which may contribute functionally to NASH progression from hepatic steatosis.
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Affiliation(s)
- Jianzhong Ye
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yishuai Lin
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qing Wang
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yating Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yajie Zhao
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lijiang Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qing Wu
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chunquan Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Cui Zhou
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yao Sun
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wanchun Ye
- Department of Chemotherapy 2, Wenzhou Central Hospital, Wenzhou, China
| | - Fumao Bai
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Fumao Bai, ; Tieli Zhou,
| | - Tieli Zhou
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Fumao Bai, ; Tieli Zhou,
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Abo El-khair SM, Ghoneim FM, Shabaan DA, Elsamanoudy AZ. Molecular and ultrastructure study of endoplasmic reticulum stress in hepatic steatosis: role of hepatocyte nuclear factor 4α and inflammatory mediators. Histochem Cell Biol 2019; 153:49-62. [PMID: 31637472 DOI: 10.1007/s00418-019-01823-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2019] [Indexed: 12/15/2022]
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40
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Yeh MM, Bosch DE, Daoud SS. Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases. World J Gastroenterol 2019; 25:4074-4091. [PMID: 31435165 PMCID: PMC6700705 DOI: 10.3748/wjg.v25.i30.4074] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/15/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte nuclear factor 4-alpha (HNF4α) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver and gastrointestinal organs (pancreas, stomach, and intestine). In liver, HNF4α is best known for its role as a master regulator of liver-specific gene expression and essential for adult and fetal liver function. Dysregulation of HNF4α expression has been associated with many human diseases such as ulcerative colitis, colon cancer, maturity-onset diabetes of the young, liver cirrhosis, and hepatocellular carcinoma. However, the precise role of HNF4α in the etiology of these human pathogenesis is not well understood. Limited information is known about the role of HNF4α isoforms in liver and gastrointestinal disease progression. There is, therefore, a critical need to know how disruption of the expression of these isoforms may impact on disease progression and phenotypes. In this review, we will update our current understanding on the role of HNF4α in human liver and gastrointestinal diseases. We further provide additional information on possible use of HNF4α as a target for potential therapeutic approaches.
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Affiliation(s)
- Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Dustin E Bosch
- Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Sayed S Daoud
- Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, WA 99210, United States
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Apelin promotes hepatic fibrosis through ERK signaling in LX-2 cells. Mol Cell Biochem 2019; 460:205-215. [PMID: 31270645 PMCID: PMC6745032 DOI: 10.1007/s11010-019-03581-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 05/27/2019] [Indexed: 02/08/2023]
Abstract
Apelin participates in cardiovascular functions, metabolic disease, and homeostasis disorder. However, the biological function of apelin in liver diseases, especially liver fibrosis is still under investigation. The present study aimed to investigate the expression of apelin in nonalcoholic fatty liver disease (NAFLD) and the mechanism of apelin promoting hepatic fibrosis through ERK signaling in hepatic stellate LX-2 cells. The results showed that the ALT and AST levels in serum were increased in the mice fed HFC. The histological staining revealed that hepatocellular steatosis and ballooning degeneration was severe, and fibrogenesis appeared as increased pericellular collagen deposition along with pericentral (lobular) collagen deposition in the mice fed HFC. Immunochemistry and qRT-PCR results showed that the expression of apelin and profibrotic genes was higher as compared to the control group. The in vitro experiments demonstrated that apelin-13 upregulated the transcription and translation levels of collagen type I (collagen-I) and α-smooth muscle actin (α-SMA) in LX-2 cells. The immunofluorescent staining, qRT-PCR, and Western blot results showed that the overexpression of apelin markedly increased the expression of α-SMA and cyclinD1. The LX-2 cells treated with apelin-13 displayed an increased expression of pERK1/2 in a time-dependent manner, while the pretreatment with PD98059 abolished the apelin-induced expression of α-SMA and cyclinD1. Furthermore, the in vivo and in vitro assays suggested a key role of apelin in promoting liver fibrosis, and the underlying mechanism might be ascribed to the apelin expression of profibrotic genes via ERK signaling pathway.
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An Y, Wang P, Xu P, Tung HC, Xie Y, Kirisci L, Xu M, Ren S, Tian X, Ma X, Xie W. An Unexpected Role of Cholesterol Sulfotransferase and its Regulation in Sensitizing Mice to Acetaminophen-Induced Liver Injury. Mol Pharmacol 2019; 95:597-605. [PMID: 30944208 PMCID: PMC6491915 DOI: 10.1124/mol.118.114819] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 03/17/2019] [Indexed: 12/13/2022] Open
Abstract
Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. The sulfotransferase-mediated sulfation of APAP is widely believed to be a protective mechanism to attenuate the hepatotoxicity of APAP. The cholesterol sulfotransferase SULT2B1b is best known for its activity in catalyzing the sulfoconjugation of cholesterol to synthesize cholesterol sulfate. SULT2B1b can be transcriptionally and positively regulated by the hepatic nuclear factor 4α (HNF4α). In this study, we uncovered an unexpected role for SULT2B1b in APAP toxicity. Hepatic overexpression of SULT2B1b sensitized mice to APAP-induced liver injury, whereas ablation of the Sult2B1b gene in mice conferred resistance to the APAP hepatotoxicity. Consistent with the notion that Sult2B1b is a transcriptional target of HNF4α, overexpression of HNF4α sensitized mice or primary hepatocytes to APAP-induced hepatotoxicity in a Sult2B1b-dependent manner. We conclude that the HNF4α-SULT2B1b axis has a unique role in APAP-induced acute liver injury, and SULT2B1b induction might be a risk factor for APAP hepatotoxicity.
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Affiliation(s)
- Yunqi An
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Pengcheng Wang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Hung-Chun Tung
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Yang Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Levent Kirisci
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Xin Tian
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Xiaochao Ma
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
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Nakatochi M, Kanai M, Nakayama A, Hishida A, Kawamura Y, Ichihara S, Akiyama M, Ikezaki H, Furusyo N, Shimizu S, Yamamoto K, Hirata M, Okada R, Kawai S, Kawaguchi M, Nishida Y, Shimanoe C, Ibusuki R, Takezaki T, Nakajima M, Takao M, Ozaki E, Matsui D, Nishiyama T, Suzuki S, Takashima N, Kita Y, Endoh K, Kuriki K, Uemura H, Arisawa K, Oze I, Matsuo K, Nakamura Y, Mikami H, Tamura T, Nakashima H, Nakamura T, Kato N, Matsuda K, Murakami Y, Matsubara T, Naito M, Kubo M, Kamatani Y, Shinomiya N, Yokota M, Wakai K, Okada Y, Matsuo H. Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals. Commun Biol 2019; 2:115. [PMID: 30993211 PMCID: PMC6453927 DOI: 10.1038/s42003-019-0339-0] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 01/22/2019] [Indexed: 01/05/2023] Open
Abstract
Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10-8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci-TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A-are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.
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Affiliation(s)
- Masahiro Nakatochi
- Data Science Division, Data Coordinating Center, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, 466-8560 Japan
| | - Masahiro Kanai
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, 565-0871 Japan
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115 USA
| | - Akiyoshi Nakayama
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, 359-8513 Japan
- Medical Squadron, Air Base Group, Western Aircraft Control and Warning Wing, Japan Air Self-Defense Force, Kasuga, 816-0804 Japan
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Yusuke Kawamura
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, 359-8513 Japan
- Department of General Medicine, National Defense Medical College, Tokorozawa, 359-8513 Japan
| | - Sahoko Ichihara
- Department of Environmental and Preventive Medicine, Jichi Medical University School of Medicine, Shimotsuke, 329-0498 Japan
| | - Masato Akiyama
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Japan
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582 Japan
| | - Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 812-8582 Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 812-8582 Japan
| | - Seiko Shimizu
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, 359-8513 Japan
| | - Ken Yamamoto
- Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, 830-0011 Japan
| | - Makoto Hirata
- Laboratory of Genome Technology, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639 Japan
| | - Rieko Okada
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Sayo Kawai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Makoto Kawaguchi
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, 359-8513 Japan
- Department of Urology, National Defense Medical College, Tokorozawa, 359-8513 Japan
| | - Yuichiro Nishida
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, 849-8501 Japan
| | - Chisato Shimanoe
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, 849-8501 Japan
| | - Rie Ibusuki
- International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8544 Japan
| | - Toshiro Takezaki
- International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8544 Japan
| | - Mayuko Nakajima
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, 359-8513 Japan
| | - Mikiya Takao
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, 359-8513 Japan
- Department of Surgery, National Defense Medical College, Tokorozawa, 359-8513 Japan
| | - Etsuko Ozaki
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, 602-8566 Japan
| | - Daisuke Matsui
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, 602-8566 Japan
| | - Takeshi Nishiyama
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8602 Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8602 Japan
| | - Naoyuki Takashima
- Department of Health Science, Shiga University of Medical Science, Otsu, 520-2192 Japan
| | - Yoshikuni Kita
- Department of Nursing, Tsuruga City College of Nursing, Fukui, 914-8501 Japan
| | - Kaori Endoh
- Laboratory of Public Health, Division of Nutritional Sciences, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, 422-8526 Japan
| | - Kiyonori Kuriki
- Laboratory of Public Health, Division of Nutritional Sciences, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, 422-8526 Japan
| | - Hirokazu Uemura
- Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503 Japan
| | - Kokichi Arisawa
- Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503 Japan
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681 Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681 Japan
- Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Yohko Nakamura
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, 260-8717 Japan
| | - Haruo Mikami
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, 260-8717 Japan
| | - Takashi Tamura
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Hiroshi Nakashima
- Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, 359-8513 Japan
| | - Takahiro Nakamura
- Laboratory for Mathematics, National Defense Medical College, Tokorozawa, 359-8513 Japan
| | - Norihiro Kato
- Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655 Japan
| | - Koichi Matsuda
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 108-8639 Japan
| | - Yoshinori Murakami
- Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639 Japan
| | - Tatsuaki Matsubara
- Department of Internal Medicine, School of Dentistry, Aichi Gakuin University, Nagoya, 464-8651 Japan
| | - Mariko Naito
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
- Department of Oral Epidemiology, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, 734-8553 Japan
| | - Michiaki Kubo
- RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Japan
| | - Yoichiro Kamatani
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Japan
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8507 Japan
| | - Nariyoshi Shinomiya
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, 359-8513 Japan
| | - Mitsuhiro Yokota
- Department of Genome Science, School of Dentistry, Aichi Gakuin University, Nagoya, 464-8651 Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Yukinori Okada
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, 565-0871 Japan
- Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, 565-0871 Japan
| | - Hirotaka Matsuo
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, 359-8513 Japan
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Hardesty JE, Wahlang B, Falkner KC, Shi H, Jin J, Zhou Y, Wilkey DW, Merchant ML, Watson CT, Feng W, Morris AJ, Hennig B, Prough RA, Cave MC. Proteomic Analysis Reveals Novel Mechanisms by Which Polychlorinated Biphenyls Compromise the Liver Promoting Diet-Induced Steatohepatitis. J Proteome Res 2019; 18:1582-1594. [PMID: 30807179 DOI: 10.1021/acs.jproteome.8b00886] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Environmental pollution contributes to fatty liver disease pathogenesis. Polychlorinated biphenyl (PCB) exposures have been associated with liver enzyme elevation and suspected steatohepatitis in cohort studies. Male mice treated with the commercial PCB mixture, Aroclor 1260 (20 mg/kg), and fed high fat diet (HFD) for 12 weeks developed steatohepatitis. Receptor-based modes of action including inhibition of the epidermal growth factor (EGF) receptor were previously proposed, but other mechanisms likely exist. Objectives were to identify and validate the pathways, transcription factors, and mechanisms responsible for the steatohepatitis associated with PCB and HFD coexposures. Comparative proteomics analysis was performed in archived mouse liver samples from the aforementioned chronic exposure study. Pathway and transcription factor analysis (TFA) was performed, and selected results were validated. Liver proteomics detected 1103 unique proteins. Aroclor 1260 upregulated 154 and downregulated 93 of these. Aroclor 1260 + HFD coexposures affected 55 pathways including glutathione metabolism, intermediary metabolism, and cytoskeletal remodeling. TFA of Aroclor 1260 treatment demonstrated alterations in the function of 42 transcription factors including downregulation of NRF2 and key nuclear receptors previously demonstrated to protect against steatohepatitis (e.g., HNF4α, FXR, PPARα/δ/γ, etc.). Validation studies demonstrated that Aroclor 1260 significantly reduced HNF4α protein levels, while Aroclor 1260 + HFD reduced expression of the HNF4α target gene, albumin, in vivo. Aroclor 1260 attenuated EGF-dependent HNF4α phosphorylation and target gene activation in vitro. Aroclor 1260 reduced levels of NRF2, its target genes, and glutathione in vivo. Aroclor 1260 attenuated EGF-dependent NRF2 upregulation, in vitro. Aroclor 1260 indirectly activated hepatic stellate cells in vitro via induction of hepatocyte-derived TGFβ. PCB exposures adversely impacted transcription factors regulating liver protection, function, and fibrosis. PCBs, thus, compromised the liver by reducing its protective responses against nutritional stress to promote diet-induced steatohepatitis. The identified mechanisms by which environmental pollutants influence fatty liver disease pathogenesis require confirmation in humans.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Andrew J Morris
- Superfund Research Center , University of Kentucky , Lexington , Kentucky 40536 , United States
| | - Bernhard Hennig
- Superfund Research Center , University of Kentucky , Lexington , Kentucky 40536 , United States
| | | | - Matthew C Cave
- The Robley Rex Veterans Affairs Medical Center , Louisville , Kentucky 40206 , United States.,The Jewish Hospital Liver Transplant Program , Louisville , Kentucky 40202 , United States
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45
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Šeda O, Cahová M, Míková I, Šedová L, Daňková H, Heczková M, Brátová M, Ďásková N, Erhartová D, Čapek V, Chylíková B, Trunečka P. Hepatic Gene Expression Profiles Differentiate Steatotic and Non-steatotic Grafts in Liver Transplant Recipients. Front Endocrinol (Lausanne) 2019; 10:270. [PMID: 31114547 PMCID: PMC6502969 DOI: 10.3389/fendo.2019.00270] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/11/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Liver transplantation leads to non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in up to 40% of graft recipients. The aim of our study was to assess transcriptomic profiles of liver grafts and to contrast the hepatic gene expression between the patients after transplantation with vs. without graft steatosis. Methods: Total RNA was isolated from liver graft biopsies of 91 recipients. Clinical characteristics were compared between steatotic (n = 48) and control (n = 43) samples. Their transcriptomic profiles were assessed using Affymetrix HuGene 2.1 ST Array Strips processed in Affymetrix GeneAtlas. Data were analyzed using Partek Genomics Suite 6.6 and Ingenuity Pathway Analysis. Results: The individuals with hepatic steatosis showed higher indices of obesity including weight, waist circumference or BMI but the two groups were comparable in measures of insulin sensitivity and cholesterol concentrations. We have identified 747 transcripts (326 upregulated and 421 downregulated in steatotic samples compared to controls) significantly differentially expressed between grafts with vs. those without steatosis. Among the most downregulated genes in steatotic samples were P4HA1, IGF1, or fetuin B while the most upregulated were PLIN1 and ME1. Most influential upstream regulators included HNF1A, RXRA, and FXR. The metabolic pathways dysregulated in steatotic liver grafts comprised blood coagulation, bile acid synthesis and transport, cell redox homeostasis, lipid and cholesterol metabolism, epithelial adherence junction signaling, amino acid metabolism, AMPK and glucagon signaling, transmethylation reactions, and inflammation-related pathways. The derived mechanistic network underlying major transcriptome differences between steatotic samples and controls featured PPARA and SERPINE1 as main nodes. Conclusions: While there is a certain overlap between the results of the current study and published transcriptomic profiles of non-transplanted livers with steatosis, we have identified discrete characteristics of the non-alcoholic fatty liver disease in liver grafts potentially utilizable for the establishment of predictive signature.
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Affiliation(s)
- Ondrej Šeda
- First Faculty of Medicine, The General University Hospital, Institute of Biology and Medical Genetics, Charles University, Prague, Czechia
| | - Monika Cahová
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
- *Correspondence: Monika Cahová
| | - Irena Míková
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Lucie Šedová
- First Faculty of Medicine, The General University Hospital, Institute of Biology and Medical Genetics, Charles University, Prague, Czechia
| | - Helena Daňková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Marie Heczková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Miriam Brátová
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Nikola Ďásková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Denisa Erhartová
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Václav Čapek
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Blanka Chylíková
- First Faculty of Medicine, The General University Hospital, Institute of Biology and Medical Genetics, Charles University, Prague, Czechia
| | - Pavel Trunečka
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czechia
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46
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Tomato Juice Supplementation Influences the Gene Expression Related to Steatosis in Rats. Nutrients 2018; 10:nu10091215. [PMID: 30200543 PMCID: PMC6165399 DOI: 10.3390/nu10091215] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 08/25/2018] [Accepted: 08/31/2018] [Indexed: 12/12/2022] Open
Abstract
The objective of this work was to identify the effect of tomato juice on the expression of genes and levels of metabolites related to steatosis in rats. Male Sprague Dawley rats (8 weeks-old) were grouped (6 rats/group) in four experimental groups: NA (normal diet and water), NL (normal diet and tomato juice), HA (high-fat diet and water), and HL (high-fat diet and tomato juice). After an intervention period of 5 weeks, rats were sacrificed and biochemical parameters, biomarkers of oxidative stress, liver metabolites, and gene expression were determined. Although the H diet provoked dislipemia related to steatosis, no changes in isoprostanes or liver malondialdehyde (MDA) were observed. Changes in the gene expression of the HA group were produced by the high consumption of fat, whereas the consumption of tomato juice had different effects, depending on the diet. In the NL group, the genes involved in β-oxidation were upregulated, and in groups NL and HL upregulation of CD36 and downregulation of APOB and LPL were observed. In addition, in the HL group the accumulation of lycopene upregulated the genes FXR and HNF4A, which have been suggested as preventive factors in relation to steatosis. Regarding the metabolomics study, intake of tomato juice stimulated the biosynthesis of glutathione and amino acids of the transulfurization pathway, increasing the levels of metabolites related to the antioxidant response.
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