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Liu H, Mei M, Lin S, Luo J, Huang S, Zhou J. Wuling San regulates AVPR2-cAMP-PKA-CREB pathway to delay cellular senescence and ameliorate acute kidney injury. JOURNAL OF ETHNOPHARMACOLOGY 2025; 347:119679. [PMID: 40216046 DOI: 10.1016/j.jep.2025.119679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 04/17/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cellular senescence in renal resident cells plays a pivotal role in the progression of acute kidney injury (AKI), necessitating the expansion of effective drug targets. Traditional Chinese medicine (TCM) formulations, characterized by their multi-target effects, offer a promising perspective for advancing research on AKI. Wuling San (WLS), a well-established compound used in treating urological disorders, has yet to elucidate its potential pharmacological targets and mechanisms in ameliorating AKI and delaying cellular senescence. AIM OF THE STUDY This study sought to elucidate the mechanisms by which WLS modulates the AVPR2-cAMP-PKA-CREB pathway to mitigate cellular senescence and promote recovery from AKI. METHODS We first prepared WLS-containing serum and performed RT-qPCR experiments to screen for GPCRs that were differentially expressed in response to WLS. Next, we established an in vitro AKI mouse model to assess the renal protective effects of the WLS by measuring renal function, renal pathology, and oxidative stress levels. After this, we performed RNA sequencing (RNA-Seq) profiling to identify differentially expressed genes (DEGs) affected by WLS treatment. We also conducted Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to identify potential signaling pathways involved. We then utilized the Gene Expression Omnibus (GEO) data to screen for cellular senescence related differentially expressed genes (CSRDEGs) in AKI patients and performed enrichment analysis, as well as a joint analysis of specific genes in relation to the RNA-Seq profiling results. We also examined how WLS affects the expression of proteins linked to cellular senescence in the AKI mouse model by targeting the AVPR2-cAMP-PKA-CREB pathway. RESULTS WLS markedly enhanced the expression of Arginine Vasopressin Receptor 2 (AVPR2) and ameliorated renal function indicators, as well as pathological changes and oxidative stress levels in the mouse model of AKI. RNA-Seq profiling revealed significant enrichment of the cAMP signaling pathway following WLS intervention. Bioinformatics analysis indicated that genes associated with cellular senescence in AKI patients were notably enriched in the p53 signaling pathway. Data mining from the GEO database, in conjunction with RNA-Seq profiling, demonstrated a substantial reduction in key genes after WLS treatment. Additionally, WLS elevated both the expression and phosphorylation of pivotal proteins within the AVPR2-cAMP-PKA-CREB pathway, while concurrently decreasing proteins associated with cellular senescence. CONCLUSION The results demonstrated that WLS significantly elevated the expression of AVPR2, which may underlie its nephroprotective effects and facilitate the mitigation of AKI by modulating the AVPR2-cAMP-PKA-CREB pathway, ultimately contributing to a delay in cellular senescence.
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Affiliation(s)
- Hong Liu
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Manxue Mei
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Shuyin Lin
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Jiahui Luo
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Sirong Huang
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Jiuyao Zhou
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
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El-Derany MO, Ramakrishnan SK, Li Y, Buscher K, Jarad CA, Schaller ML, Cantwell M, Vigil TM, Frieler RA, Sajjakulnukit P, Lyssiotis CA, Mortensen RM, Shah YM. Itaconate potentiates hepatic gluconeogenesis through NRF2 induction. PLoS One 2025; 20:e0322946. [PMID: 40323920 PMCID: PMC12052187 DOI: 10.1371/journal.pone.0322946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/31/2025] [Indexed: 05/07/2025] Open
Abstract
The interplay between systemic metabolism and immune responses is increasingly recognized as a significant factor in the dysregulation of glucose homeostasis associated with diabetes and obesity. Immune metabolites play crucial roles in mediating this crosstalk, with itaconate emerging as an important immune metabolite involved in the inflammatory response of macrophages. Recent studies have highlighted the role of itaconate as a regulator of glucose metabolism, particularly in the context of obesity, although the underlying mechanisms remain poorly understood. In this study, we identified itaconate as one of the metabolites that significantly increase in the liver during fasting compared to fed conditions. Mechanistically, we found that itaconate enhances glucagon-induced liver gluconeogenesis independently of insulin signaling. Notably, itaconate upregulates the expression of gluconeogenic genes both under basal conditions and in the presence of palmitic acid. Furthermore, our data indicate that the effects of itaconate occur independently of CREB activation. Instead, we demonstrate that these potentiating effects are mediated through the induction of nuclear factor erythroid 2-related factor 2 (NRF2). Our findings demonstrate that itaconate has a glucagon-potentiating effects in the liver, suggesting that itaconate may play a significant role in the pathogenesis of metabolic-associated liver diseases.
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Affiliation(s)
- Marwa O. El-Derany
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Sadeesh K. Ramakrishnan
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Yingjie Li
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Kathryn Buscher
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Christina A. Jarad
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Megan L. Schaller
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Marc Cantwell
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Thomas M. Vigil
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Ryan A. Frieler
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Peter Sajjakulnukit
- University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Costas A. Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
- University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Richard M. Mortensen
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Yatrik M. Shah
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America
- University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
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Mooli RGR, Mukhi D, Watt M, Nagati V, Reed SM, Gandhi NK, Oertel M, Ramakrishnan SK. Hypoxia-Inducible Factor-2α Promotes Liver Fibrosis by Inducing Hepatocellular Death. Int J Mol Sci 2024; 25:13114. [PMID: 39684823 DOI: 10.3390/ijms252313114] [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: 11/03/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
The activation of hypoxia-inducible factors (HIF)-1α and 2α in the liver is closely linked to the progression of fatty liver diseases. Prior studies indicated that disrupting hepatocyte HIF-2α attenuates diet-induced hepatic steatosis, subsequently decreasing fibrosis. However, the direct role of hepatocyte HIF-2α in liver fibrosis has not been addressed. Hepatic HIF-2α expression was examined in mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis. Conditional hepatocyte Hif-2α knockout mice were employed to investigate the role of hepatocyte HIF-2α in fibrosis. Markers of apoptosis, proliferation, inflammation, and fibrosis were assessed through biochemical, molecular, and histological analyses. We found an induction of HIF-2α in CCL4-injected liver injury and fibrosis mouse models. Hepatocyte-specific deletion of HIF-2α attenuated stellate cell activation and fibrosis, with no significant difference in inflammation. Disrupting hepatocyte HIF-2α led to reduced injury-mediated hepatocellular apoptosis. Surviving hepatocytes exhibited hypertrophy, which was strongly associated with the activation of c-JUN signaling. Our study demonstrates a direct role of hepatocyte HIF-2α in liver fibrosis by promoting hepatocyte apoptosis. The reduction in apoptosis and induction of hepatocyte hypertrophy following HIF-2α disruption is closely linked to enhanced c-JUN signaling, a survival mechanism in response to liver injury. These findings highlight HIF-2α as a potential therapeutic target for liver fibrosis.
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Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Mikayla Watt
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Veerababu Nagati
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Sara M Reed
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Nikita K Gandhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Michael Oertel
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Lu M, Xie L, Yin S, Zhou J, Yi L, Ye L. The Gut Microbial Lipid Metabolite 14(15)-EpETE Inhibits Substance P Release by Targeting GCG/PKA Signaling to Relieve Cisplatin-Induced Nausea and Vomiting in Rats. J Microbiol Biotechnol 2024; 34:1769-1777. [PMID: 39187454 PMCID: PMC11473588 DOI: 10.4014/jmb.2403.03044] [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: 03/24/2024] [Revised: 06/12/2024] [Accepted: 06/25/2024] [Indexed: 08/28/2024]
Abstract
Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect related to activation of substance P (SP). SP activation can result from dysregulation of the gut-brain axis, and also from activation of protein kinase A signaling (PKA) signaling. In this study, we connected these factors in an attempt to unveil the mechanisms underlying CINV and develop new therapeutic strategies. Female rats were injected with cisplatin (Cis) to induce pica. Fecal samples were collected before/after injection, and subjected to lipid metabolomics analysis. In another portion of pica rats, the PKA inhibitor KT5720 was applied to investigate the involvement of PKA signaling in CINV, while fecal microbiota transplantation (FMT) was implemented to verify the therapeutic effect of the lipid metabolite 14(15)-EpETE. Pica symptoms were recorded, followed by ileal histological examination. The targeting relationship between 14(15)-EpETE and glucagon was determined by bioinformatics. SP and glucagon/PKA signaling in rat ileum, serum, and/or brain substantia nigra were detected by immunohistochemistry, enzyme-linked immunosorbent assay, and/or western blot. The results showed a significantly lower level of 14(15)-EpETE in rat feces after Cis injection. KT5720 treatment alleviated Cis-induced pica symptoms, ileal injury, SP content increase in the ileum, serum, and brain substantia nigra, and ileal PKA activation in rats. The ileal level of glucagon was elevated by Cis in rats. FMT exerted an effect similar to that of KT5720 treatment, relieving the Cis-induced changes, including ileal glucagon/PKA activation in rats. Our findings demonstrate that FMT restores 14(15)-EpETE production, which inhibits SP release by targeting GCG/PKA signaling, ultimately mitigating CINV.
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Affiliation(s)
- Man Lu
- Department of Anesthesiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), No. 54 Youdian Rd., Shangcheng District, Hangzhou, Zhejiang 310006, P.R. China
| | - Liwei Xie
- Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Rd., Hangzhou, Zhejiang 310006, P.R. China
| | - Sijie Yin
- Department of Anesthesiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), No. 54 Youdian Rd., Shangcheng District, Hangzhou, Zhejiang 310006, P.R. China
| | - Jing Zhou
- Department of Anesthesiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), No. 54 Youdian Rd., Shangcheng District, Hangzhou, Zhejiang 310006, P.R. China
| | - Lingmei Yi
- Department of Anesthesiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), No. 54 Youdian Rd., Shangcheng District, Hangzhou, Zhejiang 310006, P.R. China
| | - Ling Ye
- Department of Anesthesiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), No. 54 Youdian Rd., Shangcheng District, Hangzhou, Zhejiang 310006, P.R. China
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Jeelani I, Moon JS, da Cunha FF, Nasamran CA, Jeon S, Zhang X, Bandyopadhyay GK, Dobaczewska K, Mikulski Z, Hosseini M, Liu X, Kisseleva T, Brenner D, Singh S, Loomba R, Kim M, Lee YS. HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis. Sci Transl Med 2024; 16:eadi0284. [PMID: 39259813 PMCID: PMC11665927 DOI: 10.1126/scitranslmed.adi0284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 01/12/2024] [Accepted: 08/16/2024] [Indexed: 09/13/2024]
Abstract
Proinflammatory hepatic macrophage activation plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the replacement of KCs with bone marrow-derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that hypoxia-inducible factor 2α (HIF-2α) mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2α stimulated mammalian target of rapamycin (mTOR)- and extracellular signal-regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2α-dependent TFEB regulation only occurred in KCs but not RHMs. Instead, in RHMs, HIF-2α promoted mitochondrial reactive oxygen species production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Consequently, myeloid lineage-specific or KC-specific HIF-2α depletion or the inhibition of mTOR-dependent TFEB inhibition using antisense oligonucleotide treatment protected against the development of NASH in mice. Moreover, treatment with an HIF-2α-specific inhibitor reduced inflammatory and fibrogenic gene expression in human liver spheroids cultured under a NASH-like condition. Together, our results suggest that macrophage subtype-specific effects of HIF-2α collectively contribute to the proinflammatory activation of liver macrophages, leading to the development of NASH.
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Affiliation(s)
- Ishtiaq Jeelani
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, 92093, USA
| | - Jae-Su Moon
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, 92093, USA
| | - Flavia Franco da Cunha
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, 92093, USA
| | - Chanond A. Nasamran
- Center for Computational Biology & Bioinformatics, Department of Medicine, University of California San Diego, La Jolla, California, 92093, USA
| | - Seokhyun Jeon
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, 92093, USA
| | - Xinhang Zhang
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, 92093, USA
| | - Gautam K. Bandyopadhyay
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, 92093, USA
| | - Katarzyna Dobaczewska
- Microscopy and Histology Core Facility, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
| | - Zbigniew Mikulski
- Microscopy and Histology Core Facility, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
| | - Mojgan Hosseini
- Department of Pathology, University of California San Diego School of Medicine, La Jolla, California, 92093, USA
| | - Xiao Liu
- Department of Surgery, University of California San Diego, La Jolla, California, 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, California, 92093, USA
| | - David Brenner
- Department of Medicine, University of California San Diego, La Jolla, California, 92093, USA
| | - Seema Singh
- Division of Gastroenterology, University of California San Diego, La Jolla, California, 92093, USA
| | - Rohit Loomba
- Division of Gastroenterology, University of California San Diego, La Jolla, California, 92093, USA
- Division of Epidemiology Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California, 92093, USA
- NAFLD Research Center University of California, San Diego, La Jolla, California, 92093, USA
| | - Minkyu Kim
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, 78229, USA
| | - Yun Sok Lee
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, 92093, USA
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Xia J, Chen H, Wang X, Chen W, Lin J, Xu F, Nie Q, Ye C, Zhong B, Zhao M, Yun C, Zeng G, Mao Y, Wen Y, Zhang X, Yan S, Wang X, Sun L, Liu F, Zhong C, Xia P, Jiang C, Rao H, Pang Y. Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α. Nat Commun 2024; 15:4755. [PMID: 38834568 PMCID: PMC11150497 DOI: 10.1038/s41467-024-48954-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 05/17/2024] [Indexed: 06/06/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.
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Affiliation(s)
- Jialin Xia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China
| | - Hong Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China
| | - Xiaoxiao Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Weixuan Chen
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China
| | - Jun Lin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Feng Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Qixing Nie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Chuan Ye
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Bitao Zhong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
| | - Min Zhao
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China
| | - Chuyu Yun
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China
| | - Guangyi Zeng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China
| | - Yuejian Mao
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China
| | - Yongping Wen
- Mengniu Institute of Nutrition Science, Shanghai, China
| | - Xuguang Zhang
- Mengniu Institute of Nutrition Science, Shanghai, China
- Shanghai Institute of Nutrition and Health, The Chinese Academy of Sciences, Shanghai, China
| | - Sen Yan
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China
| | - Xuemei Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Lulu Sun
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Feng Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Chao Zhong
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, China
| | - Pengyan Xia
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China.
| | - Yanli Pang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China.
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
- Institute of Advanced Clinical Medicine, Peking University, Beijing, China.
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7
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Solanki S, Shah YM. Hypoxia-Induced Signaling in Gut and Liver Pathobiology. ANNUAL REVIEW OF PATHOLOGY 2024; 19:291-317. [PMID: 37832943 DOI: 10.1146/annurev-pathmechdis-051122-094743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2023]
Abstract
Oxygen (O2) is essential for cellular metabolism and biochemical reactions. When the demand for O2 exceeds the supply, hypoxia occurs. Hypoxia-inducible factors (HIFs) are essential to activate adaptive and survival responses following hypoxic stress. In the gut (intestines) and liver, the presence of oxygen gradients or physiologic hypoxia is necessary to maintain normal homeostasis. While physiologic hypoxia is beneficial and aids in normal functions, pathological hypoxia is harmful as it exacerbates inflammatory responses and tissue dysfunction and is a hallmark of many cancers. In this review, we discuss the role of gut and liver hypoxia-induced signaling, primarily focusing on HIFs, in the physiology and pathobiology of gut and liver diseases. Additionally, we examine the function of HIFs in various cell types during gut and liver diseases, beyond intestinal epithelial and hepatocyte HIFs. This review highlights the importance of understanding hypoxia-induced signaling in the pathogenesis of gut and liver diseases and emphasizes the potential of HIFs as therapeutic targets.
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Affiliation(s)
- Sumeet Solanki
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA;
| | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA;
- University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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8
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Li YQ, Zhang LY, Zhao YC, Xu F, Hu ZY, Wu QH, Li WH, Li YN. Vascular endothelial growth factor B improves impaired glucose tolerance through insulin-mediated inhibition of glucagon secretion. World J Diabetes 2023; 14:1643-1658. [DOI: 10.4239/wjd.v14.i11.1643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/11/2023] [Accepted: 09/06/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs, insulin sensitivity decreases, causing a reduction in insulin secretion and an increase in glucagon secretion. Recently, vascular endothelial growth factor B (VEGFB) has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity. Therefore, we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion, thus contributing to the prevention and cure of prediabetes.
AIM To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.
METHODS We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression. Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay, and the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) was determined using western blot. Further, mRNA expression of forkhead box protein O1, phosphoenolpyruvate carboxykinase, and glucose-6 phosphatase was detected via quantitative polymerase chain reaction, and the correlation between the expression of proteins was analyzed via bioinformatics.
RESULTS In mice with IGT and VEGFB knockout, glucagon secretion increased, and the protein expression of PI3K/AKT decreased dramatically. Further, in mice with VEGFB overexpression, glucagon levels declined, with the activation of the PI3K/AKT signaling pathway.
CONCLUSION VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.
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Affiliation(s)
- Yu-Qi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Lu-Yang Zhang
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Fang Xu
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Zhi-Yong Hu
- School of Public Health and Management, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Qi-Hao Wu
- The First School of Clinical Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Wen-Hao Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Ya-Nuo Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
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9
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Li J, Dang P, Li Z, Zhao T, Cheng D, Pan D, Yuan Y, Song W. Peroxisomal ERK mediates Akh/glucagon action and glycemic control. Cell Rep 2023; 42:113200. [PMID: 37796662 DOI: 10.1016/j.celrep.2023.113200] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/18/2023] [Accepted: 09/15/2023] [Indexed: 10/07/2023] Open
Abstract
The enhanced response of glucagon and its Drosophila homolog, adipokinetic hormone (Akh), leads to high-caloric-diet-induced hyperglycemia across species. While previous studies have characterized regulatory components transducing linear Akh signaling promoting carbohydrate production, the spatial elucidation of Akh action at the organelle level still remains largely unclear. In this study, we find that Akh phosphorylates extracellular signal-regulated kinase (ERK) and translocates it to peroxisome via calcium/calmodulin-dependent protein kinase II (CaMKII) cascade to increase carbohydrate production in the fat body, leading to hyperglycemia. The mechanisms include that ERK mediates fat body peroxisomal conversion of amino acids into carbohydrates for gluconeogenesis in response to Akh. Importantly, Akh receptor (AkhR) or ERK deficiency, importin-associated ERK retention from peroxisome, or peroxisome inactivation in the fat body sufficiently alleviates high-sugar-diet-induced hyperglycemia. We also observe mammalian glucagon-induced hepatic ERK peroxisomal translocation in diabetic subjects. Therefore, our results conclude that the Akh/glucagon-peroxisomal-ERK axis is a key spatial regulator of glycemic control.
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Affiliation(s)
- Jiaying Li
- Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China
| | - Peixuan Dang
- Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China
| | - Zhen Li
- Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China
| | - Tujing Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, China
| | - Daojun Cheng
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, China
| | - Dingyu Pan
- Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China.
| | - Yufeng Yuan
- Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China.
| | - Wei Song
- Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China.
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10
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Dagdeviren S, Hoang MF, Sarikhani M, Meier V, Benoit JC, Okawa MC, Melnik VY, Ricci-Blair EM, Foot N, Friedline RH, Hu X, Tauer LA, Srinivasan A, Prigozhin MB, Shenoy SK, Kumar S, Kim JK, Lee RT. An insulin-regulated arrestin domain protein controls hepatic glucagon action. J Biol Chem 2023; 299:105045. [PMID: 37451484 PMCID: PMC10413355 DOI: 10.1016/j.jbc.2023.105045] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 06/16/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023] Open
Abstract
Glucagon signaling is essential for maintaining normoglycemia in mammals. The arrestin fold superfamily of proteins controls the trafficking, turnover, and signaling of transmembrane receptors as well as other intracellular signaling functions. Further investigation is needed to understand the in vivo functions of the arrestin domain-containing 4 (ARRDC4) protein family member and whether it is involved in mammalian glucose metabolism. Here, we show that mice with a global deletion of the ARRDC4 protein have impaired glucagon responses and gluconeogenesis at a systemic and molecular level. Mice lacking ARRDC4 exhibited lower glucose levels after fasting and could not suppress gluconeogenesis at the refed state. We also show that ARRDC4 coimmunoprecipitates with the glucagon receptor, and ARRDC4 expression is suppressed by insulin. These results define ARRDC4 as a critical regulator of glucagon signaling and glucose homeostasis and reveal a novel intersection of insulin and glucagon pathways in the liver.
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Affiliation(s)
- Sezin Dagdeviren
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Megan F Hoang
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Mohsen Sarikhani
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Vanessa Meier
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Jake C Benoit
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Marinna C Okawa
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Veronika Y Melnik
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Elisabeth M Ricci-Blair
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Natalie Foot
- Centre for Cancer Biology, University of South Australia, Adelaide, Australia
| | - Randall H Friedline
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Xiaodi Hu
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Lauren A Tauer
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Arvind Srinivasan
- Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA
| | - Maxim B Prigozhin
- Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA; John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
| | - Sudha K Shenoy
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, Australia
| | - Jason K Kim
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
| | - Richard T Lee
- Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
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11
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Cao R, Tian H, Zhang Y, Liu G, Xu H, Rao G, Tian Y, Fu X. Signaling pathways and intervention for therapy of type 2 diabetes mellitus. MedComm (Beijing) 2023; 4:e283. [PMID: 37303813 PMCID: PMC10248034 DOI: 10.1002/mco2.283] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 04/18/2023] [Accepted: 04/27/2023] [Indexed: 06/13/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID-19). T2DM is characterized by insulin resistance (IR) and pancreatic β cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and β cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.
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Affiliation(s)
- Rong Cao
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Huimin Tian
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yu Zhang
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Geng Liu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Haixia Xu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Guocheng Rao
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yan Tian
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Xianghui Fu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
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12
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Hrabalova P, Bohuslavova R, Matejkova K, Papousek F, Sedmera D, Abaffy P, Kolar F, Pavlinkova G. Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy. Cardiovasc Diabetol 2023; 22:88. [PMID: 37072781 PMCID: PMC10114478 DOI: 10.1186/s12933-023-01824-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 04/03/2023] [Indexed: 04/20/2023] Open
Abstract
BACKGROUND An altered sympathetic nervous system is implicated in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia, cardiac arrhythmias, myocardial infarction, and heart failure. Although the mechanisms responsible for disruption of this well-organized system are the subject of intensive investigations, the exact processes controlling the cardiac sympathetic nervous system are still not fully understood. A conditional knockout of the Hif1a gene was reported to affect the development of sympathetic ganglia and sympathetic innervation of the heart. This study characterized how the combination of HIF-1α deficiency and streptozotocin (STZ)-induced diabetes affects the cardiac sympathetic nervous system and heart function of adult animals. METHODS Molecular characteristics of Hif1a deficient sympathetic neurons were identified by RNA sequencing. Diabetes was induced in Hif1a knockout and control mice by low doses of STZ treatment. Heart function was assessed by echocardiography. Mechanisms involved in adverse structural remodeling of the myocardium, i.e. advanced glycation end products, fibrosis, cell death, and inflammation, was assessed by immunohistological analyses. RESULTS We demonstrated that the deletion of Hif1a alters the transcriptome of sympathetic neurons, and that diabetic mice with the Hif1a-deficient sympathetic system have significant systolic dysfunction, worsened cardiac sympathetic innervation, and structural remodeling of the myocardium. CONCLUSIONS We provide evidence that the combination of diabetes and the Hif1a deficient sympathetic nervous system results in compromised cardiac performance and accelerated adverse myocardial remodeling, associated with the progression of diabetic cardiomyopathy.
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Affiliation(s)
- Petra Hrabalova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology CAS, BIOCEV, Vestec, Czechia
- Charles University, Prague, Czechia
| | - Romana Bohuslavova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology CAS, BIOCEV, Vestec, Czechia
| | - Katerina Matejkova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology CAS, BIOCEV, Vestec, Czechia
| | | | - David Sedmera
- Institute of Physiology CAS, Prague, Czechia
- Institute of Anatomy, Charles University, Prague, Czechia
| | - Pavel Abaffy
- Laboratory of Gene Expression, Institute of Biotechnology CAS, BIOCEV, Vestec, Czechia
| | | | - Gabriela Pavlinkova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology CAS, BIOCEV, Vestec, Czechia.
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13
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Wang J, Wang J, Wang Y, Ma R, Zhang S, Zheng J, Xue W, Ding X. Bone Marrow Mesenchymal Stem Cells-Derived miR-21-5p Protects Grafted Islets Against Apoptosis by Targeting PDCD4. Stem Cells 2022; 41:169-183. [PMID: 36512434 PMCID: PMC9982070 DOI: 10.1093/stmcls/sxac085] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 12/01/2022] [Indexed: 12/15/2022]
Abstract
The apoptosis of grafted islets is an urgent problem due to the high rate of islet loss soon after transplantation. MicroRNA-21-5p (miR-21-5p) is an essential mediator of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exo) during anti-apoptosis, but its effect and the underlying molecular mechanism in islet transplantation remain partially understood. Here, we found that miR-21-5p could be delivered to islet cells via BMSCs-Exo. Subsequently, we demonstrated that miR-21-5p overexpression reduced apoptosis in islets and INS-1 cells, whereas miR-21-5p inhibition enhanced apoptosis. A mechanistic analysis involving RNA sequencing and bioinformatic analysis was performed to determine the interaction between miR-21-5p and its target gene programmed cell death 4 (PDCD4), which was further verified by a dual luciferase assay. In vivo, the grafted islets overexpressing miR-21-5p showed a higher survival rate, better insulin secretion function, and a lower apoptosis rate. In conclusion, these results demonstrated that miR‑21‑5p from BMSCs-Exo protects against the apoptosis of grafted islets by inhibiting PDCD4 expression. Hence, miR-21-5p can be used as a cell-free therapeutic agent to minimize β-cell apoptosis at the early stage of islet transplantation.
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Affiliation(s)
| | | | - Ying Wang
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Ruiyang Ma
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Shucong Zhang
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Jin Zheng
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Wujun Xue
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Xiaoming Ding
- Corresponding author: Xiaoming Ding, Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China. Tel: +8613991238632; E-mail:
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14
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Ekwudo MN, Malek MC, Anderson CE, Yampolsky LY. The interplay between prior selection, mild intermittent exposure, and acute severe exposure in phenotypic and transcriptional response to hypoxia. Ecol Evol 2022; 12:e9319. [PMID: 36248677 PMCID: PMC9548574 DOI: 10.1002/ece3.9319] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/01/2022] [Accepted: 09/02/2022] [Indexed: 11/16/2022] Open
Abstract
Hypoxia has profound and diverse effects on aerobic organisms, disrupting oxidative phosphorylation and activating several protective pathways. Predictions have been made that exposure to mild intermittent hypoxia may be protective against more severe exposure and may extend lifespan. Here we report the lifespan effects of chronic, mild, intermittent hypoxia, and short-term survival in acute severe hypoxia in four clones of Daphnia magna originating from either permanent or intermittent habitats. We test the hypothesis that acclimation to chronic mild intermittent hypoxia can extend lifespan through activation of antioxidant and stress-tolerance pathways and increase survival in acute severe hypoxia through activation of oxygen transport and storage proteins and adjustment to carbohydrate metabolism. Unexpectedly, we show that chronic hypoxia extended the lifespan in the two clones originating from intermittent habitats but had the opposite effect in the two clones from permanent habitats, which also showed lower tolerance to acute hypoxia. Exposure to chronic hypoxia did not protect against acute hypoxia; to the contrary, Daphnia from the chronic hypoxia treatment had lower acute hypoxia tolerance than normoxic controls. Few transcripts changed their abundance in response to the chronic hypoxia treatment in any of the clones. After 12 h of acute hypoxia treatment, the transcriptional response was more pronounced, with numerous protein-coding genes with functionality in oxygen transport, mitochondrial and respiratory metabolism, and gluconeogenesis, showing upregulation. While clones from intermittent habitats showed somewhat stronger differential expression in response to acute hypoxia than those from permanent habitats, contrary to predictions, there were no significant hypoxia-by-habitat of origin or chronic-by-acute treatment interactions. GO enrichment analysis revealed a possible hypoxia tolerance role by accelerating the molting cycle and regulating neuron survival through upregulation of cuticular proteins and neurotrophins, respectively.
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Affiliation(s)
- Millicent N. Ekwudo
- Department of Biological SciencesEast Tennessee State UniversityJohnson CityTennesseeUSA
- Ann Romney Center for Neurologic Diseases, Brigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | - Morad C. Malek
- Department of Biological SciencesEast Tennessee State UniversityJohnson CityTennesseeUSA
| | - Cora E. Anderson
- Department of Biological SciencesEast Tennessee State UniversityJohnson CityTennesseeUSA
- Department of Biological SciencesUniversity of Notre DameNotre DameIndianaUSA
| | - Lev Y. Yampolsky
- Department of Biological SciencesEast Tennessee State UniversityJohnson CityTennesseeUSA
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15
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Moon JS, Riopel M, Seo JB, Herrero-Aguayo V, Isaac R, Lee YS. HIF-2α Preserves Mitochondrial Activity and Glucose Sensing in Compensating β-Cells in Obesity. Diabetes 2022; 71:1508-1524. [PMID: 35472707 PMCID: PMC9233300 DOI: 10.2337/db21-0736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 04/08/2022] [Indexed: 11/13/2022]
Abstract
In obesity, increased mitochondrial metabolism with the accumulation of oxidative stress leads to mitochondrial damage and β-cell dysfunction. In particular, β-cells express antioxidant enzymes at relatively low levels and are highly vulnerable to oxidative stress. Early in the development of obesity, β-cells exhibit increased glucose-stimulated insulin secretion in order to compensate for insulin resistance. This increase in β-cell function under the condition of enhanced metabolic stress suggests that β-cells possess a defense mechanism against increased oxidative damage, which may become insufficient or decline at the onset of type 2 diabetes. Here, we show that metabolic stress induces β-cell hypoxia inducible factor 2α (HIF-2α), which stimulates antioxidant gene expression (e.g., Sod2 and Cat) and protects against mitochondrial reactive oxygen species (ROS) and subsequent mitochondrial damage. Knockdown of HIF-2α in Min6 cells exaggerated chronic high glucose-induced mitochondrial damage and β-cell dysfunction by increasing mitochondrial ROS levels. Moreover, inducible β-cell HIF-2α knockout mice developed more severe β-cell dysfunction and glucose intolerance on a high-fat diet, along with increased ROS levels and decreased islet mitochondrial mass. Our results provide a previously unknown mechanism through which β-cells defend against increased metabolic stress to promote β-cell compensation in obesity.
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Affiliation(s)
- Jae-Su Moon
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Matthew Riopel
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Jong Bae Seo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Vicente Herrero-Aguayo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Maimonides Institute of Biomedical Research of Cordoba, Cordoba, Spain
| | - Roi Isaac
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Yun Sok Lee
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Corresponding author: Yun Sok Lee,
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16
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Xia QS, Wu F, Wu WB, Dong H, Huang ZY, Xu L, Lu FE, Gong J. Berberine reduces hepatic ceramide levels to improve insulin resistance in HFD-fed mice by inhibiting HIF-2α. Biomed Pharmacother 2022; 150:112955. [PMID: 35429745 DOI: 10.1016/j.biopha.2022.112955] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/05/2022] [Accepted: 04/08/2022] [Indexed: 11/24/2022] Open
Abstract
Several studies have documented the effects of hypoxia and ceramides on lipid and glucose metabolism, resulting in insulin resistance. However, the roles of ceramide in hepatic hypoxia and hepatic insulin resistance remain to be clarified. This study aimed to explore the relationship between hypoxia, ceramide synthesis, and hepatic insulin resistance in high-fat diet (HFD)-fed mice. Given the interaction of hypoxia-inducible factors 2α(HIF-2α) and berberine determined using molecular docking, this study also assessed the pharmacological effects of berberine on the HIF-2α-ceramide-insulin resistance pathway. In the preliminary phase of the study, gradually aggravated hepatic hypoxia and varying levels of ceramides were observed with the development of type 2 diabetes mellitus (T2DM) due to increasing HIF-2α accumulation. Lipidomic analyses of animal and cell models revealed that berberine reduced hypoxia-induced ceramide production and attenuated ceramide-induced insulin resistance. This research provides timely and necessary evidence for the role of ceramide in hypoxia and insulin resistance in the liver. It also contributes to a better understanding of the pharmacological effects of berberine on ameliorating hypoxia and insulin resistance in T2DM therapy.
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Affiliation(s)
- Qing-Song Xia
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Fan Wu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wen-Bin Wu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Hui Dong
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhao-Yi Huang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Lijun Xu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Fu-Er Lu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
| | - Jing Gong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
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Zhang A, Huang Z, Tao W, Zhai K, Wu Q, Rich JN, Zhou W, Bao S. USP33 deubiquitinates and stabilizes HIF-2alpha to promote hypoxia response in glioma stem cells. EMBO J 2022; 41:e109187. [PMID: 35191554 PMCID: PMC8982626 DOI: 10.15252/embj.2021109187] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 12/17/2022] Open
Abstract
Hypoxia regulates tumor angiogenesis, metabolism, and therapeutic response in malignant cancers including glioblastoma, the most lethal primary brain tumor. The regulation of HIF transcriptional factors by the ubiquitin-proteasome system is critical in the hypoxia response, but hypoxia-inducible deubiquitinases that counteract the ubiquitination remain poorly defined. While the activation of ERK1/2 also plays an important role in hypoxia response, the relationship between ERK1/2 activation and HIF regulation remains elusive. Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. USP33 is preferentially induced in glioma stem cells by hypoxia and interacts with HIF-2alpha, leading to its stabilization through deubiquitination. The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33. Silencing of USP33 disrupted glioma stem cells maintenance, reduced tumor vascularization, and inhibited glioblastoma growth. Our findings highlight USP33 as an essential regulator of hypoxia response in cancer stem cells, indicating a novel potential therapeutic target for brain tumor treatment.
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Affiliation(s)
- Aili Zhang
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Zhi Huang
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Weiwei Tao
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Kui Zhai
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Qiulian Wu
- Hillman Cancer CenterUniversity of Pittsburgh Medical CenterPittsburghPAUSA
| | - Jeremy N Rich
- Hillman Cancer CenterUniversity of Pittsburgh Medical CenterPittsburghPAUSA
| | - Wenchao Zhou
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA
| | - Shideng Bao
- Department of Cancer BiologyLerner Research InstituteCleveland ClinicClevelandOHUSA,Case Comprehensive Cancer CenterCase Western Reserve University School of MedicineClevelandOHUSA,Center for Cancer Stem Cell ResearchLerner Research InstituteCleveland ClinicClevelandOHUSA
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18
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Mooli RGR, Mukhi D, Pasupulati AK, Evers SS, Sipula IJ, Jurczak M, Seeley RJ, Shah YM, Ramakrishnan SK. Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells. Cell Mol Gastroenterol Hepatol 2021; 13:1057-1072. [PMID: 34902628 PMCID: PMC8873605 DOI: 10.1016/j.jcmgh.2021.12.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/04/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Compelling evidence shows that glucagon-like peptide-1 (GLP-1) has a profound effect in restoring normoglycemia in type 2 diabetic patients by increasing pancreatic insulin secretion. Although L-cells are the primary source of circulating GLP-1, the current therapies do not target L-cells to increase GLP-1 levels. Our study aimed to determine the molecular underpinnings of GLP-1 secretion as an impetus to identify new interventions to target endogenous L-cells. METHODS We used genetic mouse models of intestine-specific overexpression of hypoxia-inducible factor (HIF)-1α and HIF-2α (VhlΔIE), conditional overexpression of intestinal HIF-2α (Hif-2αLSL;Vilin-Cre/ERT2), and intestine-specific HIF-2α knockout mice (Hif-2αΔIE) to show that HIF signaling, especially HIF-2α, regulates GLP-1 secretion. RESULTS Our data show that intestinal HIF signaling improved glucose homeostasis in a GLP-1-dependent manner. Intestinal HIF potentiated GLP-1 secretion via the lipid sensor G-protein-coupled receptor (GPR)40 enriched in L-cells. We show that HIF-2α regulates GPR40 in L-cells and potentiates fatty acid-induced GLP-1 secretion via extracellular regulated kinase (ERK). Using a genetic model of intestine-specific overexpression of HIF-2α, we show that HIF-2α is sufficient to increase GLP-1 levels and attenuate diet-induced metabolic perturbations such as visceral adiposity, glucose intolerance, and hepatic steatosis. Lastly, we show that intestinal HIF-2α signaling acts as a priming mechanism crucial for postprandial lipid-mediated GLP-1 secretion. Thus, disruption of intestinal HIF-2α decreases GLP-1 secretion. CONCLUSIONS In summary, we show that intestinal HIF signaling, particularly HIF-2α, regulates the lipid sensor GPR40, which is crucial for the lipid-mediated GLP-1 secretion, and suggest that HIF-2α is a potential target to induce endogenous GLP-1 secretion.
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Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Anil K Pasupulati
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Ian J Sipula
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael Jurczak
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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19
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Zhang Y, Wu T, Li W, Zhao Y, Long H, Liu R, Sui W, Zhang M. Lactobacillus casei LC89 exerts antidiabetic effects through regulating hepatic glucagon response and gut microbiota in type 2 diabetic mice. Food Funct 2021; 12:8288-8299. [PMID: 34308462 DOI: 10.1039/d1fo00882j] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Previous study suggests that Lactobacillus casei exhibits antihyperglycemic activity, however, the molecular mechanism of this has yet to be elucidated. Here, the anti-diabetic effects and underlying mechanisms of Lactobacillus casei LC89 are investigated in type 2 diabetes mellitus (T2DM) mice, which was induced by a high-fat diet (HFD) with streptozotocin (100 mg per kg BW). The results show that LC89 at a dose of 109 CFU day-1 decreases fasting blood glucose (FBG) and insulin levels by 35.12% and 28.37%, respectively, compared to the diabetes control (DC) group. Moreover, LC89 treatment improved the insulin resistance index (HOMA-IR), serum lipid profiles and inflammation cytokines. The real-time polymerase chain reaction indicated that LC89 markedly downregulates the mRNA expression of hepatic glucagon (GCG), glucagon receptor (GCGR), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Meanwhile, LC89 significantly decreases the abundance of Odoribacter, but increases the Alloprevotella, Bacteroides, Parabacteroides and Ruminococcus content. Therefore, LC89 plays a positive role in alleviating T2DM by regulating gut microbiota and glucagon signal pathway-related genes, and it may be a beneficial dietary supplement to regulate glucose metabolism in T2DM.
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Affiliation(s)
- Yongli Zhang
- Key Laboratory of Food Nutrition and Safety, Ministry of Education & Tianjin Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Tao Wu
- Key Laboratory of Food Nutrition and Safety, Ministry of Education & Tianjin Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Wen Li
- Key Laboratory of Food Nutrition and Safety, Ministry of Education & Tianjin Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Yunjiao Zhao
- Key Laboratory of Food Nutrition and Safety, Ministry of Education & Tianjin Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Hairong Long
- Key Laboratory of Food Nutrition and Safety, Ministry of Education & Tianjin Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, Tianjin University of Science & Technology, Tianjin 300457, China. and Guangxi Botanical Garden of Medicinal Plants, Nanning, Guangxi 530023, China
| | - Rui Liu
- Key Laboratory of Food Nutrition and Safety, Ministry of Education & Tianjin Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Wenjie Sui
- Key Laboratory of Food Nutrition and Safety, Ministry of Education & Tianjin Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, Tianjin University of Science & Technology, Tianjin 300457, China.
| | - Min Zhang
- Key Laboratory of Food Nutrition and Safety, Ministry of Education & Tianjin Key Laboratory of Food Nutrition and Safety, Food Biotechnology Engineering Research Center of Ministry of Education, Tianjin University of Science & Technology, Tianjin 300457, China. and Tianjin Agricultural University, Tianjin 300384, China
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20
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Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis. Cells 2021; 10:cells10071764. [PMID: 34359934 PMCID: PMC8305108 DOI: 10.3390/cells10071764] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 12/18/2022] Open
Abstract
Liver fibrosis is a potentially reversible pathophysiological event, leading to excess deposition of extracellular matrix (ECM) components and taking place as the net result of liver fibrogenesis, a dynamic and highly integrated process occurring during chronic liver injury of any etiology. Liver fibrogenesis and fibrosis, together with chronic inflammatory response, are primarily involved in the progression of chronic liver diseases (CLD). As is well known, a major role in fibrogenesis and fibrosis is played by activated myofibroblasts (MFs), as well as by macrophages and other hepatic cell populations involved in CLD progression. In the present review, we will focus the attention on the emerging pathogenic role of hypoxia, hypoxia-inducible factors (HIFs) and related mediators in the fibrogenic progression of CLD.
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21
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Abstract
Mammals undergo regular cycles of fasting and feeding that engage dynamic transcriptional responses in metabolic tissues. Here we review advances in our understanding of the gene regulatory networks that contribute to hepatic responses to fasting and feeding. The advent of sequencing and -omics techniques have begun to facilitate a holistic understanding of the transcriptional landscape and its plasticity. We highlight transcription factors, their cofactors, and the pathways that they impact. We also discuss physiological factors that impinge on these responses, including circadian rhythms and sex differences. Finally, we review how dietary modifications modulate hepatic gene expression programs.
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Affiliation(s)
- Lara Bideyan
- Department of Pathology and Laboratory Medicine, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA.,Department of Biological Chemistry, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA
| | - Rohith Nagari
- Department of Pathology and Laboratory Medicine, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA.,Department of Biological Chemistry, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA.,Department of Biological Chemistry, and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA
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22
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Kietzmann T, Mäkelä VH. The hypoxia response and nutritional peptides. Peptides 2021; 138:170507. [PMID: 33577839 DOI: 10.1016/j.peptides.2021.170507] [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: 12/15/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 10/22/2022]
Abstract
Hypoxia controls metabolism at several levels, e.g., via mitochondrial ATP production, glucose uptake and glycolysis. Hence it is likely that hypoxia also affects the action and/or production of many peptide hormones linked to food intake and appetite control. Many of those are produced in the gastrointestinal tract, endocrine pancreas, adipose tissue, and selective areas in the brain which modulate and concert their actions. However, the complexity of the hypoxia response and the links to peptides/hormones involved in food intake and appetite control in the different organs are not well known. This review summarizes the role of the hypoxia response and its effects on major peptides linked to appetite regulation, nutrition and metabolism.
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Affiliation(s)
- Thomas Kietzmann
- University of Oulu, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, Oulu, Finland.
| | - Ville H Mäkelä
- University of Oulu, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, Oulu, Finland
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23
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Mooli RGR, Rodriguez J, Takahashi S, Solanki S, Gonzalez FJ, Ramakrishnan SK, Shah YM. Hypoxia via ERK Signaling Inhibits Hepatic PPARα to Promote Fatty Liver. Cell Mol Gastroenterol Hepatol 2021; 12:585-597. [PMID: 33798787 PMCID: PMC8258975 DOI: 10.1016/j.jcmgh.2021.03.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 03/17/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Fatty liver or nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with comorbidities such as insulin resistance and cardiovascular and metabolic diseases. Chronic activation of hypoxic signaling, in particular, hypoxia-inducible factor (HIF)2α, promotes NAFLD progression by repressing genes involved in fatty acid β-oxidation through unclear mechanisms. Therefore, we assessed the precise mechanism by which HIF2α promotes fatty liver and its physiological relevance in metabolic homeostasis. METHODS Primary hepatocytes from VHL (VhlΔHep) and PPARα (Ppara-null) knockout mice that were loaded with fatty acids, murine dietary protocols to induce hepatic steatosis, and fasting-refeeding dietary regimen approaches were used to test our hypothesis. RESULTS Inhibiting autophagy using chloroquine did not decrease lipid contents in VhlΔHep primary hepatocytes. Inhibition of ERK using MEK inhibitor decreased lipid contents in primary hepatocytes from a genetic model of constitutive HIF activation and primary hepatocytes loaded with free fatty acids. Moreover, MEK-ERK inhibition potentiated ligand-dependent activation of PPARα. We also show that MEK-ERK inhibition improved diet-induced hepatic steatosis, which is associated with the induction of PPARα target genes. During fasting, fatty acid β-oxidation is induced by PPARα, and refeeding inhibits β-oxidation. Our data show that ERK is involved in the post-prandial repression of hepatic PPARα signaling. CONCLUSIONS Overall, our results demonstrate that ERK activated by hypoxia signaling plays a crucial role in fatty acid β-oxidation genes by repressing hepatocyte PPARα signaling.
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Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jessica Rodriguez
- Department of Molecular and Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Shogo Takahashi
- Departments of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, District of Columbia; National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sumeet Solanki
- Department of Molecular and Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Frank J Gonzalez
- National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Molecular and Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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24
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Abstract
Hypoxia can be defined as a relative deficiency in the amount of oxygen reaching the tissues. Hypoxia-inducible factors (HIFs) are critical regulators of the mammalian response to hypoxia. In normal circumstances, HIF-1α protein turnover is rapid, and hyperglycemia further destabilizes the protein. In addition to their role in diabetes pathogenesis, HIFs are implicated in development of the microvascular and macrovascular complications of diabetes. Improving glucose control in people with diabetes increases HIF-1α protein and has wide-ranging benefits, some of which are at least partially mediated by HIF-1α. Nevertheless, most strategies to improve diabetes or its complications via regulation of HIF-1α have not currently proven to be clinically useful. The intersection of HIF biology with diabetes is a complex area in which many further questions remain, especially regarding the well-conducted studies clearly describing discrepant effects of different methods of increasing HIF-1α, even within the same tissues. This Review presents a brief overview of HIFs; discusses the range of evidence implicating HIFs in β cell dysfunction, diabetes pathogenesis, and diabetes complications; and examines the differing outcomes of HIF-targeting approaches in these conditions.
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Affiliation(s)
- Jenny E Gunton
- Centre for Diabetes, Obesity and Endocrinology, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.,Westmead Hospital, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
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25
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Fillebeen C, Lam NH, Chow S, Botta A, Sweeney G, Pantopoulos K. Regulatory Connections between Iron and Glucose Metabolism. Int J Mol Sci 2020; 21:ijms21207773. [PMID: 33096618 PMCID: PMC7589414 DOI: 10.3390/ijms21207773] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 10/07/2020] [Accepted: 10/16/2020] [Indexed: 02/06/2023] Open
Abstract
Iron is essential for energy metabolism, and states of iron deficiency or excess are detrimental for organisms and cells. Therefore, iron and carbohydrate metabolism are tightly regulated. Serum iron and glucose levels are subjected to hormonal regulation by hepcidin and insulin, respectively. Hepcidin is a liver-derived peptide hormone that inactivates the iron exporter ferroportin in target cells, thereby limiting iron efflux to the bloodstream. Insulin is a protein hormone secreted from pancreatic β-cells that stimulates glucose uptake and metabolism via insulin receptor signaling. There is increasing evidence that systemic, but also cellular iron and glucose metabolic pathways are interconnected. This review article presents relevant data derived primarily from mouse models and biochemical studies. In addition, it discusses iron and glucose metabolism in the context of human disease.
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Affiliation(s)
- Carine Fillebeen
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC H3Y 1P3, Canada;
| | - Nhat Hung Lam
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Samantha Chow
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Amy Botta
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Gary Sweeney
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (N.H.L.); (S.C.); (A.B.); (G.S.)
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC H3Y 1P3, Canada;
- Correspondence: ; Tel.: +1-514-340-8260 (ext. 25293)
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26
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Pirri D, Fragiadaki M, Evans PC. Diabetic atherosclerosis: is there a role for the hypoxia-inducible factors? Biosci Rep 2020; 40:BSR20200026. [PMID: 32816039 PMCID: PMC7441368 DOI: 10.1042/bsr20200026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 07/28/2020] [Accepted: 08/07/2020] [Indexed: 12/11/2022] Open
Abstract
Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors, including diabetes. Diabetes is associated with either an insulin deficiency in its juvenile form or with insulin resistance and obesity in Type 2 diabetes mellitus, and the latter is clustered with other comorbidities to define the metabolic syndrome. Diabetes and metabolic syndrome are complex pathologies and are associated with cardiovascular risk via vascular inflammation and other mechanisms. Several transcription factors are activated upon diabetes-driven endothelial dysfunction and drive the progression of atherosclerosis. In particular, the hypoxia-inducible factor (HIF) transcription factor family is a master regulator of endothelial biology and is raising interest in the field of atherosclerosis. In this review, we will present an overview of studies contributing to the understanding of diabetes-driven atherosclerosis, integrating the role of HIF in this disease with the knowledge of its functions in metabolic syndrome and diabetic scenario.
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Affiliation(s)
- Daniela Pirri
- Department of Infection, Immunity and Cardiovascular disease, The University of Sheffield, U.K
- Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Maria Fragiadaki
- Department of Infection, Immunity and Cardiovascular disease, The University of Sheffield, U.K
| | - Paul C. Evans
- Department of Infection, Immunity and Cardiovascular disease, The University of Sheffield, U.K
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27
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Riopel M, Moon JS, Bandyopadhyay GK, You S, Lam K, Liu X, Kisseleva T, Brenner D, Lee YS. Inhibition of prolyl hydroxylases increases hepatic insulin and decreases glucagon sensitivity by an HIF-2α-dependent mechanism. Mol Metab 2020; 41:101039. [PMID: 32534258 PMCID: PMC7393408 DOI: 10.1016/j.molmet.2020.101039] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023] Open
Abstract
Objective Recent evidence indicates that inhibition of prolyl hydroxylase domain (PHD) proteins can exert beneficial effects to improve metabolic abnormalities in mice and humans. However, the underlying mechanisms are not clearly understood. This study was designed to address this question. Methods A pan-PHD inhibitor compound was injected into WT and liver-specific hypoxia-inducible factor (HIF)-2α KO mice, after onset of obesity and glucose intolerance, and changes in glucose and glucagon tolerance were measured. Tissue-specific changes in basal glucose flux and insulin sensitivity were also measured by hyperinsulinemic euglycemic clamp studies. Molecular and cellular mechanisms were assessed in normal and type 2 diabetic human hepatocytes, as well as in mouse hepatocytes. Results Administration of a PHD inhibitor compound (PHDi) after the onset of obesity and insulin resistance improved glycemic control by increasing insulin and decreasing glucagon sensitivity in mice, independent of body weight change. Hyperinsulinemic euglycemic clamp studies revealed that these effects of PHDi treatment were mainly due to decreased basal hepatic glucose output and increased liver insulin sensitivity. Hepatocyte-specific deletion of HIF-2α markedly attenuated these effects of PHDi treatment, showing PHDi effects are HIF-2α dependent. At the molecular level, HIF-2α induced increased Irs2 and cyclic AMP-specific phosphodiesterase gene expression, leading to increased and decreased insulin and glucagon signaling, respectively. These effects of PHDi treatment were conserved in human and mouse hepatocytes. Conclusions Our results elucidate unknown mechanisms for how PHD inhibition improves glycemic control through HIF-2α-dependent regulation of hepatic insulin and glucagon sensitivity.
PHD inhibitor treatment improves glycemic control in obese glucose-intolerant mice. PHD inhibitor treatment decreases liver glucagon sensitivity in obese mice. The effects of PHD inhibition on glycemic control is hepatocyte HIF-2α-dependent. PHD inhibitor treatment stimulates HIF-2α-dependent cAMP-specific PDE expression. In human and mouse hepatocytes, PHD inhibitor treatment suppresses glucagon signaling.
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Affiliation(s)
- Matthew Riopel
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Jae-Su Moon
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Gautam K Bandyopadhyay
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Seohee You
- Cardiovascular and Metabolism, Janssen Research & Development, Spring House, PA, USA
| | - Kevin Lam
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
| | - Xiao Liu
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Yun Sok Lee
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
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Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism. Cell Metab 2019; 30:937-951.e5. [PMID: 31668872 DOI: 10.1016/j.cmet.2019.09.016] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 07/10/2019] [Accepted: 09/26/2019] [Indexed: 12/18/2022]
Abstract
Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis.
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Zhang WS, Pan A, Zhang X, Ying A, Ma G, Liu BL, Qi LW, Liu Q, Li P. Inactivation of NF-κB2 (p52) restrains hepatic glucagon response via preserving PDE4B induction. Nat Commun 2019; 10:4303. [PMID: 31541100 PMCID: PMC6754499 DOI: 10.1038/s41467-019-12351-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 09/05/2019] [Indexed: 12/17/2022] Open
Abstract
Glucagon promotes hepatic gluconeogenesis and maintains whole-body glucose levels during fasting. The regulatory factors that are involved in fasting glucagon response are not well understood. Here we report a role of p52, a key activator of the noncanonical nuclear factor-kappaB signaling, in hepatic glucagon response. We show that p52 is activated in livers of HFD-fed and glucagon-challenged mice. Knockdown of p52 lowers glucagon-stimulated hyperglycemia, while p52 overexpression augments glucagon response. Mechanistically, p52 binds to phosphodiesterase 4B promoter to inhibit its transcription and promotes cAMP accumulation, thus augmenting the glucagon response through cAMP/PKA signaling. The anti-diabetic drug metformin and ginsenoside Rb1 lower blood glucose at least in part by inhibiting p52 activation. Our findings reveal that p52 mediates glucagon-triggered hepatic gluconeogenesis and suggests that pharmacological intervention to prevent p52 processing is a potential therapeutic strategy for diabetes. Elevated glucagon level in obesity and diabetes promotes hepatic glucose production and hyperglycemia. Here the authors report that NF-κB2 augments the hepatic glucagon responses by inhibiting PDE4B induction, and that metformin lowers blood glucose in part by inhibiting NF-κB2.
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Affiliation(s)
- Wen-Song Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - An Pan
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xu Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Ang Ying
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Gaoxiang Ma
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.,Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, 211198, China
| | - Bao-Lin Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Lian-Wen Qi
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. .,Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, 211198, China.
| | - Qun Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Ping Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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30
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Sinturel F, Makhlouf AM, Meyer P, Tran C, Pataky Z, Golay A, Rey G, Howald C, Dermitzakis ET, Pichard C, Philippe J, Brown SA, Dibner C. Cellular circadian period length inversely correlates with HbA 1c levels in individuals with type 2 diabetes. Diabetologia 2019; 62:1453-1462. [PMID: 31134308 DOI: 10.1007/s00125-019-4907-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/17/2019] [Indexed: 10/26/2022]
Abstract
AIMS/HYPOTHESIS The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes. METHODS We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters. RESULTS We observed a significant inverse correlation (ρ = -0.592; p < 0.05) between HbA1c values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression. CONCLUSIONS/INTERPRETATION We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans. DATA AVAILABILITY RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.
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Affiliation(s)
- Flore Sinturel
- Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland
| | - Anne-Marie Makhlouf
- Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland
| | - Patrick Meyer
- Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland
| | - Christel Tran
- Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland
- Center for Molecular Diseases, Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Zoltan Pataky
- Division for Therapeutic Patient Education for Chronic Diseases, University Hospital of Geneva, Geneva, Switzerland
| | - Alain Golay
- Division for Therapeutic Patient Education for Chronic Diseases, University Hospital of Geneva, Geneva, Switzerland
| | - Guillaume Rey
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Cédric Howald
- Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Emmanouil T Dermitzakis
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Claude Pichard
- Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland
| | - Jacques Philippe
- Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Steven A Brown
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Charna Dibner
- Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, 14, Geneva, Switzerland.
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
- Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
- Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.
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Lee YS, Riopel M, Cabrales P, Bandyopadhyay GK. Hepatocyte-specific HIF-1α ablation improves obesity-induced glucose intolerance by reducing first-pass GLP-1 degradation. SCIENCE ADVANCES 2019; 5:eaaw4176. [PMID: 31281892 PMCID: PMC6609217 DOI: 10.1126/sciadv.aaw4176] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 05/30/2019] [Indexed: 05/04/2023]
Abstract
The decrease in incretin effects is an important etiologic component of type 2 diabetes with unknown mechanisms. In an attempt to understand obesity-induced changes in liver oxygen homeostasis, we found that liver HIF-1α expression was increased mainly by soluble factors released from obese adipocytes, leading to decreased incretin effects. Deletion of hepatocyte HIF-1α protected obesity-induced glucose intolerance without changes in body weight, liver steatosis, or insulin resistance. In-depth mouse metabolic phenotyping revealed that obesity increased first-pass degradation of an incretin hormone GLP-1 with increased liver DPP4 expression and decreased sinusoidal blood flow rate, reducing active GLP-1 levels in peripheral circulation. Hepatocyte HIF-1α KO blocked these changes induced by obesity. Deletion of hepatocyte HIF-2α did not change liver DPP4 expression but improved hepatic steatosis. Our results identify a previously unknown pathway for obesity-induced impaired beta cell glucose response (incretin effects) and the development of glucose intolerance through inter-organ communications.
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Affiliation(s)
- Yun Sok Lee
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Matthew Riopel
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Pedro Cabrales
- Department of Engineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Guatam K. Bandyopadhyay
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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32
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33
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Wang L, Vanacker C, Burger LL, Barnes T, Shah YM, Myers MG, Moenter SM. Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction. eLife 2019; 8:e43999. [PMID: 30946012 PMCID: PMC6491090 DOI: 10.7554/elife.43999] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 04/02/2019] [Indexed: 12/12/2022] Open
Abstract
The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedbacks are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest that activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.
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Affiliation(s)
- Luhong Wang
- Department of Molecular and Integrative PhysiologyUniversity of MichiganAnn ArborUnited States
| | - Charlotte Vanacker
- Department of Molecular and Integrative PhysiologyUniversity of MichiganAnn ArborUnited States
| | - Laura L Burger
- Department of Molecular and Integrative PhysiologyUniversity of MichiganAnn ArborUnited States
| | - Tammy Barnes
- Department of Internal MedicineUniversity of MichiganAnn ArborUnited States
| | - Yatrik M Shah
- Department of Molecular and Integrative PhysiologyUniversity of MichiganAnn ArborUnited States
| | - Martin G Myers
- Department of Molecular and Integrative PhysiologyUniversity of MichiganAnn ArborUnited States
- Department of Internal MedicineUniversity of MichiganAnn ArborUnited States
| | - Suzanne M Moenter
- Department of Internal MedicineUniversity of MichiganAnn ArborUnited States
- Department of Obstetrics & GynecologyUniversity of MichiganAnn ArborUnited States
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PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin. Proc Natl Acad Sci U S A 2019; 116:4285-4290. [PMID: 30770439 PMCID: PMC6410797 DOI: 10.1073/pnas.1815150116] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression.
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35
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Schwartz AJ, Das NK, Ramakrishnan SK, Jain C, Jurkovic MT, Wu J, Nemeth E, Lakhal-Littleton S, Colacino JA, Shah YM. Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload. J Clin Invest 2018; 129:336-348. [PMID: 30352047 DOI: 10.1172/jci122359] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 10/16/2018] [Indexed: 01/22/2023] Open
Abstract
Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin, a liver-derived hormone that controls iron mobilization through its molecular target ferroportin (FPN), the only known mammalian iron exporter. This pathway is perturbed in diseases that cause iron overload. Additionally, intestinal HIF-2α is essential for the local absorptive response to systemic iron deficiency and iron overload. Our data demonstrate a hetero-tissue crosstalk mechanism, whereby hepatic hepcidin regulated intestinal HIF-2α in iron deficiency, anemia, and iron overload. We show that FPN controlled cell-autonomous iron efflux to stabilize and activate HIF-2α by regulating the activity of iron-dependent intestinal prolyl hydroxylase domain enzymes. Pharmacological blockade of HIF-2α using a clinically relevant and highly specific inhibitor successfully treated iron overload in a mouse model. These findings demonstrate a molecular link between hepatic hepcidin and intestinal HIF-2α that controls physiological iron uptake and drives iron hyperabsorption during iron overload.
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Affiliation(s)
| | - Nupur K Das
- Department of Molecular and Integrative Physiology, and
| | | | - Chesta Jain
- Department of Molecular and Integrative Physiology, and
| | | | - Jun Wu
- Department of Molecular and Integrative Physiology, and.,Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA
| | - Elizabeta Nemeth
- Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
| | - Samira Lakhal-Littleton
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | | | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, and.,Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
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36
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Abstract
Hypoxia-inducible factors (HIFs), a family of transcription factors activated by hypoxia, consist of three α-subunits (HIF1α, HIF2α and HIF3α) and one β-subunit (HIF1β), which serves as a heterodimerization partner of the HIFα subunits. HIFα subunits are stabilized from constitutive degradation by hypoxia largely through lowering the activity of the oxygen-dependent prolyl hydroxylases that hydroxylate HIFα, leading to their proteolysis. HIF1α and HIF2α are expressed in different tissues and regulate target genes involved in angiogenesis, cell proliferation and inflammation, and their expression is associated with different disease states. HIFs have been widely studied because of their involvement in cancer, and HIF2α-specific inhibitors are being investigated in clinical trials for the treatment of kidney cancer. Although cancer has been the major focus of research on HIF, evidence has emerged that this pathway has a major role in the control of metabolism and influences metabolic diseases such as obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease. Notably increased HIF1α and HIF2α signalling in adipose tissue and small intestine, respectively, promotes metabolic diseases in diet-induced disease models. Inhibition of HIF1α and HIF2α decreases the adverse diet-induced metabolic phenotypes, suggesting that they could be drug targets for the treatment of metabolic diseases.
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Affiliation(s)
- Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
| | - Cen Xie
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
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37
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Gaspar JM, Mendes NF, Corrêa-da-Silva F, Lima-Junior JCD, Gaspar RC, Ropelle ER, Araujo EP, Carvalho HM, Velloso LA. Downregulation of HIF complex in the hypothalamus exacerbates diet-induced obesity. Brain Behav Immun 2018; 73:550-561. [PMID: 29935943 DOI: 10.1016/j.bbi.2018.06.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/30/2018] [Accepted: 06/20/2018] [Indexed: 11/25/2022] Open
Abstract
Hypothalamic hypoxia-inducible factor-1 (HIF-1) can regulate whole-body energy homeostasis in response to changes in blood glucose, suggesting that it acts as a sensor for systemic energy stores. Here, we hypothesized that hypothalamic HIF-1 could be affected by diet-induced obesity (DIO). We used eight-week old, male C57Bl6 mice, fed normal chow diet or with high fat diet for 1, 3, 7, 14 and 28 days. The expression of HIF-1alpha and HIF-1beta was measured by PCR and western blotting and its hypothalamic distribution was evaluated by fluorescence microscopy. Inhibition of HIF-1beta in arcuate nucleus of hypothalamus was performed using stereotaxic injection of shRNA lentiviral particles and animals were grouped under normal chow diet or high fat diet for 14 days. Using bioinformatics, we show that in humans, the levels of HIF-1 transcripts are directly correlated with those of hypothalamic transcripts for proteins involved in inflammation, regulation of apoptosis, autophagy, and the ubiquitin/proteasome system; furthermore, in rodents, hypothalamic HIF-1 expression is directly correlated with the phenotype of increased energy expenditure. In mice, DIO was accompanied by increased HIF-1 expression. The inhibition of hypothalamic HIF-1 by injection of an shRNA resulted in a further increase in body mass, a decreased basal metabolic rate, increased hypothalamic inflammation, and glucose intolerance. Thus, hypothalamic HIF-1 is increased during DIO, and its inhibition worsens the obesity-associated metabolic phenotype. Thus, hypothalamic HIF-1 emerges as a target for therapeutic intervention against obesity.
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Affiliation(s)
- Joana M Gaspar
- Laboratory of Cell Signaling, University of Campinas, Obesity and Comorbidities Research Center, Campinas, São Paulo, Brazil
| | - Natália Ferreira Mendes
- Laboratory of Cell Signaling, University of Campinas, Obesity and Comorbidities Research Center, Campinas, São Paulo, Brazil; Faculty of Nursing, University of Campinas, Campinas, São Paulo, Brazil
| | - Felipe Corrêa-da-Silva
- Laboratory of Cell Signaling, University of Campinas, Obesity and Comorbidities Research Center, Campinas, São Paulo, Brazil
| | - José C de Lima-Junior
- Laboratory of Cell Signaling, University of Campinas, Obesity and Comorbidities Research Center, Campinas, São Paulo, Brazil
| | - Rodrigo C Gaspar
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Eduardo R Ropelle
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Eliana P Araujo
- Laboratory of Cell Signaling, University of Campinas, Obesity and Comorbidities Research Center, Campinas, São Paulo, Brazil; Faculty of Nursing, University of Campinas, Campinas, São Paulo, Brazil
| | - Humberto M Carvalho
- Department of Physical Education, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Lício A Velloso
- Laboratory of Cell Signaling, University of Campinas, Obesity and Comorbidities Research Center, Campinas, São Paulo, Brazil.
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Wei J, Yuan Y, Chen L, Xu Y, Zhang Y, Wang Y, Yang Y, Peek CB, Diebold L, Yang Y, Gao B, Jin C, Melo-Cardenas J, Chandel NS, Zhang DD, Pan H, Zhang K, Wang J, He F, Fang D. ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes. Nat Commun 2018; 9:3659. [PMID: 30201971 PMCID: PMC6131148 DOI: 10.1038/s41467-018-06091-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 04/27/2018] [Indexed: 12/21/2022] Open
Abstract
The HMG-CoA reductase degradation protein 1 (HRD1) has been identified as a key enzyme for endoplasmic reticulum-associated degradation of misfolded proteins, but its organ-specific physiological functions remain largely undefined. Here we show that mice with HRD1 deletion specifically in the liver display increased energy expenditure and are resistant to HFD-induced obesity and liver steatosis and insulin resistance. Proteomic analysis identifies a HRD1 interactome, a large portion of which includes metabolic regulators. Loss of HRD1 results in elevated ENTPD5, CPT2, RMND1, and HSD17B4 protein levels and a consequent hyperactivation of both AMPK and AKT pathways. Genome-wide mRNA sequencing revealed that HRD1-deficiency reprograms liver metabolic gene expression profiles, including suppressing genes involved in glycogenesis and lipogenesis and upregulating genes involved in glycolysis and fatty acid oxidation. We propose HRD1 as a liver metabolic regulator and a potential drug target for obesity, fatty liver disease, and insulin resistance associated with the metabolic syndrome.
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Affiliation(s)
- Juncheng Wei
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Yanzhi Yuan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 102206, Beijing, China
| | - Lu Chen
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China
| | - Yuanming Xu
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Yuehui Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 102206, Beijing, China
| | - Yajun Wang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Yanjie Yang
- Department of Medical Psychology, Public Health Institute of Harbin Medical University, 150081, Harbin, China
| | - Clara Bien Peek
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Lauren Diebold
- Department of Medicine, Northwestern University Feinberg School of Mdicine, Chicago, IL, 60611, USA
| | - Yi Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Beixue Gao
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Chaozhi Jin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 102206, Beijing, China
| | - Johanna Melo-Cardenas
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Navdeep S Chandel
- Department of Medicine, Northwestern University Feinberg School of Mdicine, Chicago, IL, 60611, USA
| | - Donna D Zhang
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA
| | - Hui Pan
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Jian Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 102206, Beijing, China.
| | - Fuchu He
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 102206, Beijing, China.
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
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Jiménez-Jiménez C, Lara-Chica M, Palomares B, Collado JA, Lopez-Miranda J, Muñoz E, Calzado MA. Effect of N-acyl-dopamines on beta cell differentiation and wound healing in diabetic mice. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1865:1539-1551. [PMID: 30327197 DOI: 10.1016/j.bbamcr.2018.08.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 08/12/2018] [Accepted: 08/14/2018] [Indexed: 12/19/2022]
Abstract
N-acyl-dopamines are endolipids with neuroprotective, antiinflammatory and immunomodulatory properties. Previously, we showed the ability of these compounds to induce HIF-1α stabilization. Hypoxia and HIF-1α play an important role in the most relevant stages of diabetic pathogenesis. This work analyzes the possible role of these molecules on beta cell differentiation, insulin production and diabetic foot ulcer. Hypoxia response pathway has been characterized in beta-cell differentiation in rat pancreatic acinar cell line and human islet-derived precursor cells. Protein and mRNA expression of key proteins in this process have been analyzed, as well as those involved in beta cells reprogramming. The effect of N-acyl-dopamines on hypoxia response pathway, beta cells reprogramming and insulin production have been studied in both cell types, as well as its role in angiogenesis models in vitro and wound closure in type 2 diabetic mice. Our results show how the hypoxia response pathway is altered during beta cells differentiation, accompanied by an induction of the transcription factor HIF-1α. We demonstrate how some N-acyl-dopamines induce beta cell differentiation and insulin production in two different cell models. In parallel, these endolipids promote angiogenesis in vitro and wound closure in type 2 diabetic mice. These results provide a biological mechanism through which some endolipids could induce beta cell differentiation. We demonstrate how N-acyl-dopamines can modulate insulin production and, in parallel, reverse HIF-1α inhibition in a wound healing model in diabetic mice. Therefore, the potential use of the pharmacological modulation of N-acyl-dopamines may have implications for diabetes prevention and treatment strategies.
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Affiliation(s)
- Carla Jiménez-Jiménez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
| | - Maribel Lara-Chica
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
| | - Belén Palomares
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
| | - Juan Antonio Collado
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
| | - J Lopez-Miranda
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; Unidad de lípidos y aterosclerosis, Hospital Universitario Reina Sofía, Córdoba, Universidad de Córdoba, Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain
| | - Eduardo Muñoz
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
| | - Marco A Calzado
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain.
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Xie W, Ye Y, Feng Y, Xu T, Huang S, Shen J, Leng Y. Linderane Suppresses Hepatic Gluconeogenesis by Inhibiting the cAMP/PKA/CREB Pathway Through Indirect Activation of PDE 3 via ERK/STAT3. Front Pharmacol 2018; 9:476. [PMID: 29867482 PMCID: PMC5962748 DOI: 10.3389/fphar.2018.00476] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 04/23/2018] [Indexed: 12/22/2022] Open
Abstract
The role of phosphodiesterase 3 (PDE3), a cyclic AMP (cAMP)-degrading enzyme, in modulating gluconeogenesis remains unknown. Here, linderane, a natural compound, was found to inhibit gluconeogenesis by activating hepatic PDE3 in rat primary hepatocytes. The underlying molecular mechanism and its effects on whole-body glucose and lipid metabolism were investigated. The effect of linderane on gluconeogenesis, cAMP content, phosphorylation of cAMP-response element-binding protein (CREB) and PDE activity were examined in cultured primary hepatocytes and C57BL/6J mice. The precise mechanism by which linderane activates PDE3 and inhibits the cAMP pathway was explored using pharmacological inhibitors. The amelioration of metabolic disorders was observed in ob/ob mice. Linderane inhibited gluconeogenesis, reduced phosphoenolpyruvate carboxykinase (Pck1) and glucose-6-phosphatase (G6pc) gene expression, and decreased intracellular cAMP concentration and CREB phosphorylation in rat primary hepatocytes under both basal and forskolin-stimulated conditions. In rat primary hepatocytes, it also increased total PDE and PDE3 activity but not PDE4 activity. The suppressive effect of linderane on the cAMP pathway and gluconeogenesis was abolished by the non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the specific PDE3 inhibitor cilostazol. Linderane indirectly activated PDE3 through extracellular regulated protein kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) activation. Linderane improved glucose and lipid metabolism after chronic oral administration in ob/ob mice. Our findings revealed linderane as an indirect PDE3 activator that suppresses gluconeogenesis through cAMP pathway inhibition and has beneficial effects on metabolic syndromes in ob/ob mice. This investigation highlighted the potential for PDE3 activation in the treatment of type 2 diabetes.
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Affiliation(s)
- Wei Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yangliang Ye
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Ying Feng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Tifei Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Suling Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Jianhua Shen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Ying Leng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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41
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Ramakrishnan SK, Shah YM. A central role for hypoxia-inducible factor (HIF)-2α in hepatic glucose homeostasis. ACTA ACUST UNITED AC 2017; 4:207-216. [PMID: 29276790 PMCID: PMC5734117 DOI: 10.3233/nha-170022] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatic glucose production is regulated by hormonal and dietary factors. At fasting, 80% of glucose released into the circulation is derived from the liver, among which gluconeogenesis accounts for 55% and the rest by glycogenolysis. Studies suggest a complex mechanism involved in the regulation of hepatic glucose metabolism during fasting and post-absorptive phase. Oxygen plays a key role in numerous metabolic pathways such as TCA cycle, gluconeogenesis, glycolysis and fatty acid oxidation. Oxygenation of the gastrointestinal tract including liver and intestine is dynamically regulated by changes in the blood flow and metabolic activity. Cellular adaptation to low oxygen is mediated by the transcription factors HIF-1α and HIF-2α. HIF-1α regulates glycolytic genes whereas HIF-2α is known to primarily regulate genes involved in cell proliferation and iron metabolism. This review focuses on the role of the oxygen sensing signaling in the regulation of hepatic glucose output with an emphasis on hypoxia inducible factor (HIF)-2α. Recent studies have established a metabolic role of HIF-2α in systemic glucose homeostasis. Understanding the HIF-2α dependent mechanism in hepatic metabolism will greatly enhance our potential to utilize the oxygen sensing mechanisms to treat metabolic diseases.
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Affiliation(s)
- Sadeesh K Ramakrishnan
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.,Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA
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42
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Xie C, Yagai T, Luo Y, Liang X, Chen T, Wang Q, Sun D, Zhao J, Ramakrishnan SK, Sun L, Jiang C, Xue X, Tian Y, Krausz KW, Patterson AD, Shah YM, Wu Y, Jiang C, Gonzalez FJ. Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis. Nat Med 2017; 23:1298-1308. [PMID: 29035368 PMCID: PMC6410352 DOI: 10.1038/nm.4412] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 08/29/2017] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice. PT2385, a HIF-2α-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2α. Intestine HIF-2α inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2α regulates ceramide metabolism mainly from the salvage pathway, by positively regulating the expression of Neu3, the gene encoding neuraminidase 3. These results suggest that intestinal HIF-2α could be a viable target for hepatic steatosis therapy.
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Affiliation(s)
- Cen Xie
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Tomoki Yagai
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Yuhong Luo
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Xianyi Liang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Tao Chen
- Department of Internal Medicine, Key Laboratory of Environment and Genes Related to Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Qiong Wang
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Dongxue Sun
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Jie Zhao
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Sadeesh K Ramakrishnan
- Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Lulu Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Chunmei Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Xiang Xue
- Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Yuan Tian
- Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Yatrik M Shah
- Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Yue Wu
- Department of Internal Medicine, Key Laboratory of Environment and Genes Related to Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- These authors jointly directed this work
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- These authors jointly directed this work
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43
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Meng F, Zhang W, Wang Y. RASAL1 inhibits HepG2 cell growth via HIF-2α mediated gluconeogenesis. Oncol Lett 2017; 14:7344-7352. [PMID: 29344173 PMCID: PMC5755015 DOI: 10.3892/ol.2017.7123] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/24/2017] [Indexed: 01/01/2023] Open
Abstract
RAS protein activator like 1 (RASAL1) is a member of the RAS GTPase-activating protein (GAP) family, and has been identified as a tumor suppressor in various types of cancer. In the present study, it was determined that decreased levels of RASAL1 were accompanied by a higher pathological stage and larger tumor size in human liver cancer. Therefore, it was hypothesized that RASAL1 may serve an inhibitory role in liver cancer. In the present study, the following was demonstrated: i) Exogenous expression of RASAL1 may inhibit the proliferation and invasion ability of HepG2 cells; ii) overexpression of RASAL1 may downregulate HIF-2α transcription activity and HIF-2α-mediated gluconeogenesis through extracellular signal-related kinase 1/2 activation; iii) RASAL1 may reduce the xenograft tumor size in nude mice by inhibiting the expression of hypoxia-inducible factor (HIF)-2α and gluconeogenesis enzymes. These data suggest that the RASAL1/HIF-2α axis may serve an essential role in the growth of HepG2 cells, and that this signaling cascade may be a novel therapeutic target for the treatment of liver cancer.
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Affiliation(s)
- Fanhua Meng
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276000, P.R. China
| | - Wei Zhang
- Department of Electrocardiography, Linyi People's Hospital, Linyi, Shandong 276000, P.R. China
| | - Yufeng Wang
- Department of Ultrasonography, Linyi People's Hospital, Linyi, Shandong 276000, P.R. China
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Yadav H, Devalaraja S, Chung ST, Rane SG. TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis. J Biol Chem 2017; 292:3420-3432. [PMID: 28069811 DOI: 10.1074/jbc.m116.764910] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/04/2017] [Indexed: 12/21/2022] Open
Abstract
Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.
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Affiliation(s)
- Hariom Yadav
- Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854
| | - Samir Devalaraja
- Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854
| | - Stephanie T Chung
- Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854
| | - Sushil G Rane
- Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20854.
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Yan K, Gao LN, Cui YL, Zhang Y, Zhou X. The cyclic AMP signaling pathway: Exploring targets for successful drug discovery (Review). Mol Med Rep 2016; 13:3715-23. [PMID: 27035868 PMCID: PMC4838136 DOI: 10.3892/mmr.2016.5005] [Citation(s) in RCA: 139] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 02/08/2016] [Indexed: 12/03/2022] Open
Abstract
During development of disease, complex intracellular signaling pathways regulate an intricate series of events, including resistance to external toxins, the secretion of cytokines and the production of pathological phenomena. Adenosine 3′,5′-cyclic monophosphate (cAMP) is a nucleotide that acts as a key second messenger in numerous signal transduction pathways. cAMP regulates various cellular functions, including cell growth and differentiation, gene transcription and protein expression. This review aimed to provide an understanding of the effects of the cAMP signaling pathway and the associated factors on disease occurrence and development by examining the information from a new perspective. These novel insights aimed to promote the development of novel therapeutic approaches and aid in the development of new drugs.
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Affiliation(s)
- Kuo Yan
- Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
| | - Li-Na Gao
- Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
| | - Yuan-Lu Cui
- Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
| | - Yi Zhang
- Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
| | - Xin Zhou
- Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
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