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Jia W, Li Y, Cheung KCP, Zheng X. Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis. SCIENCE CHINA. LIFE SCIENCES 2024; 67:865-878. [PMID: 37515688 DOI: 10.1007/s11427-023-2353-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 04/23/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BAs) play a crucial role in nutrient absorption and act as key regulators of lipid and glucose metabolism and immune homeostasis. Through the enterohepatic circulation, BAs are synthesized, metabolized, and reabsorbed, with a portion entering the vascular circulation and distributing systemically. This allows BAs to interact with receptors in all major organs, leading to organ-organ interactions that regulate both local and global metabolic processes, as well as the immune system. This review focuses on the whole-body effects of BA-mediated metabolic and immunological regulation, including in the brain, heart, liver, intestine, eyes, skin, adipose tissue, and muscle. Targeting BA synthesis and receptor signaling is a promising strategy for the development of novel therapies for various diseases throughout the body.
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Affiliation(s)
- Wei Jia
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Yitao Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Kenneth C P Cheung
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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Wang J, Zhu G. A precise prognostic signature in CTNNB1-mutant hepatocellular carcinoma: Prognosis prediction and precision treatment exploration. Heliyon 2023; 9:e22382. [PMID: 38125518 PMCID: PMC10730442 DOI: 10.1016/j.heliyon.2023.e22382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 09/27/2023] [Accepted: 11/10/2023] [Indexed: 12/23/2023] Open
Abstract
Background CTNNB1 mutates in most hepatocellular carcinoma (HCC) which is the most familiar form of liver cancer with high heterogeneity. It is critical to create a specific prognostication methodology and to investigate additional treatment options for CTNNB1-mutant HCCs. Methods A total of 926 samples in five independent cohorts were enrolled in this study, including 127 CTNNB1-mutant samples and 75 estimated CTNNB1-mutant samples. The prognostic signature was constructed by LASSO-Cox regression and evaluated by bioinformatics analyses. The selection of possible drug targets and agents was produced based on the expression profiles and drug sensitivity data of cancer cell lines in two databases. Results A prognostic signature based on 15 genes categorized the CTNNB1-mutant HCCs into two groups with different risks. Compared to low-risk patients, high-risk patients had significantly inferior prognoses. ROC curve and multivariate analysis also indicated the superior performance of our signature on the prognosis estimation, particularly in CTNNB1-mutant HCCs. Besides, the nomogram was constructed according to the prognostic signature with excellent predictive performance confirmed by the calibration curve. Subsequently, we suggested that AT-7519 and PHA-793887 might be potential drug agents for high-risk patients. Conclusion We established a 15-gene prognostic model, particularly in HCCs with CTNNB1 mutations with good predictive efficiency. Besides, we explored the potential drug targets and agents for patients with high risk. Our findings offered a fresh idea for personalized prognosis management in HCCs with CTNNB1 mutations and threw new insight for precise treatment in HCCs as well.
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Affiliation(s)
- Junying Wang
- Department of Interventional and Vascular Surgery, Zhongda Hospital, Southeast University, Jiangsu, 210009, China
| | - Guangyu Zhu
- Department of Interventional and Vascular Surgery, Zhongda Hospital, Southeast University, Jiangsu, 210009, China
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Luo B, Xu W, Feng L, Chen J, Shi R, Cao H. Association Between Visceral Fat Area and Glycated Hemoglobin in Type 2 Diabetics: A Retrospective Study. Diabetes Metab Syndr Obes 2023; 16:3295-3301. [PMID: 37900621 PMCID: PMC10606363 DOI: 10.2147/dmso.s425166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 10/11/2023] [Indexed: 10/31/2023] Open
Abstract
Introduction Obesity is a risk factor for the development of type 2 diabetes (T2DM) as well as its associated metabolic complications. Central obesity, characterized by an increased visceral fat area (VFA), is contributed to the development of T2DM. However, the relationship between VFA and HbA1c is not particularly clear. Methods A total of 3173 patients with T2DM participated in the study at the Metabolic Management Center (MMC), with anthropometric and biochemical measurements recorded. To examine the association between HbA1c and VFA, fitting curves were plotted, facilitating a comprehensive observation of their relationship. Results HbA1c was inversely associated with VFA (β -1.79, 95% CI -2.34~-1.24, P < 0.001). The fitted curve shows that VFA increased with the increase of HbA1c when it was less than 8.62%. When it was greater than 8.62%, VFA decreased as HbA1c increased. Using linear inflection point analysis, we found that its inflection point interval falls within 8.36%~8.88%. Conclusion VFA was positively associated with HbA1c in individuals with T2DM. Furthermore, the relationship between the two variables was an inverted U-shaped association.
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Affiliation(s)
- Beibei Luo
- Clinical Laboratory, People’s Hospital of Yuxi City, Yuxi City, Yunnan Province, People’s Republic of China
| | - Wenbo Xu
- Clinical Laboratory, People’s Hospital of Yuxi City, Yuxi City, Yunnan Province, People’s Republic of China
| | - Lei Feng
- Clinical Laboratory, Yan’an Hospital of Kunming City, Kunming City, Yunnan Province, People’s Republic of China
| | - Jingyi Chen
- Clinical Laboratory, People’s Hospital of Yuxi City, Yuxi City, Yunnan Province, People’s Republic of China
| | - Rui Shi
- Department of Laboratory, The Sixth Affiliated Hospital of Kunming Medical University, Yuxi City, Yunnan Province, People’s Republic of China
| | - Huiying Cao
- Clinical Laboratory, Yan’an Hospital of Kunming City, Kunming City, Yunnan Province, People’s Republic of China
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Zhao M, Okunishi K, Bu Y, Kikuchi O, Wang H, Kitamura T, Izumi T. Targeting activin receptor-like kinase 7 ameliorates adiposity and associated metabolic disorders. JCI Insight 2023; 8:161229. [PMID: 36626233 PMCID: PMC9977491 DOI: 10.1172/jci.insight.161229] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Activin receptor-like kinase 7 (ALK7) is a type I receptor in the TGF-β superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to both genetic and diet-induced obesity. Human genetic studies have recently revealed an association between ALK7 variants and both reduced waist to hip ratios and resistance to development of diabetes. In the present study, treatment with a neutralizing mAb against ALK7 caused a substantial loss of adipose mass and improved glucose intolerance and insulin resistance in both genetic and diet-induced mouse obesity models. The enhanced lipolysis increased fatty acid supply from adipocytes to promote fatty acid oxidation in muscle and oxygen consumption at the whole-body level. The treatment temporarily increased hepatic triglyceride levels, which resolved with long-term Ab treatment. Blocking of ALK7 signals also decreased production of its ligand, growth differentiation factor 3, by downregulating S100A8/A9 release from adipocytes and, subsequently, IL-1β release from adipose tissue macrophages. These findings support the feasibility of potential therapeutics targeting ALK7 as a treatment for obesity and diabetes.
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Affiliation(s)
- Min Zhao
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, and
| | - Katsuhide Okunishi
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, and
| | - Yun Bu
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, and
| | - Osamu Kikuchi
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Hao Wang
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, and
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Tetsuro Izumi
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, and
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Li S, Feng F, Deng Y. Resveratrol Regulates Glucose and Lipid Metabolism in Diabetic Rats by Inhibition of PDK1/AKT Phosphorylation and HIF-1α Expression. Diabetes Metab Syndr Obes 2023; 16:1063-1074. [PMID: 37090841 PMCID: PMC10115207 DOI: 10.2147/dmso.s403893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 04/07/2023] [Indexed: 04/25/2023] Open
Abstract
Purpose To explore the underlying mechanism of the anti-diabetic effect of resveratrol (RSV) on regulating glycolipid metabolism in diabetic rats induced by streptozotocin (STZ) and a high-fat diet (HFD). Methods Male Wistar rats were randomized into three groups. Two groups were fed a high-fat diet and intraperitoneally injected with STZ (35 mg/kg), with one group also treated with RSV (30 mg/kg/d), and the third, control group was fed a normal diet. After 12 weeks, blood lipid levels and fasting blood glucose (FBG) were assessed. Histopathological changes were evaluated by hematoxylin-eosin (HE) staining and periodic acid-Schiff (PAS) staining. The protein expression of hypoxia-inducible factor 1α (HIF-1α) was assessed by Western blotting and immunofluorescence, and the proteins level of 3-phosphoinositide-dependent protein kinase 1 (PDK1), phosphorylated-PDK1 (p-PDK1), phosphorylated-protein kinase B (p-AKT), glucose transporter 1 (GLUT1) and low-density lipoprotein receptor (LDLR) in the liver were analyzed by Western blotting. The mRNA levels of Hif-1α, Glut1 and Ldlr in the liver were determined by RT-qPCR. Results RSV treatment significantly reduced liver/body weight ratio (L/W, P < 0.05), FBG (P < 0.01) and serum concentrations of total cholesterol (TC, P < 0.05), triglycerides (TG, P < 0.01) and low-density lipoprotein-cholesterol (LDL-C, P < 0.05) in diabetic rats. RSV also improved diabetic symptoms, attenuated liver steatosis and increased liver glycogen accumulation. RSV treatment significantly downregulated the proteins expression of p-PDK1 and p-AKT (P < 0.01) and the levels of HIF-1α (P < 0.05) and GLUT1 (P < 0.01), while significantly upregulating the level of LDLR (P < 0.05). Conclusion RSV was effective in improving glycolipid metabolism in diabetic rats, probably by inhibiting the PDK1/AKT/HIF-1α pathway and regulation of its downstream target levels. These findings may provide new insight into the mechanism of action of RSV in the treatment of diabetes.
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Affiliation(s)
- Siyun Li
- Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, People’s Republic of China
| | - Fuzhen Feng
- Department of Pharmacy, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, People’s Republic of China
| | - Yanhui Deng
- Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, People’s Republic of China
- Correspondence: Yanhui Deng, Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Road, Tianhe District, Guangzhou, 510630, People’s Republic of China, Tel +86 020 62784810, Email
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Wang J, Lu P, Xie W. Atypical functions of xenobiotic receptors in lipid and glucose metabolism. MEDICAL REVIEW (2021) 2022; 2:611-624. [PMID: 36785576 PMCID: PMC9912049 DOI: 10.1515/mr-2022-0032] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 11/08/2022] [Indexed: 12/02/2022]
Abstract
Xenobiotic receptors are traditionally defined as xenobiotic chemical-sensing receptors, the activation of which transcriptionally regulates the expression of enzymes and transporters involved in the metabolism and disposition of xenobiotics. Emerging evidence suggests that "xenobiotic receptors" also have diverse endobiotic functions, including their effects on lipid metabolism and energy metabolism. Dyslipidemia is a major risk factor for cardiovascular disease, diabetes, obesity, metabolic syndrome, stroke, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Understanding the molecular mechanism by which transcriptional factors, including the xenobiotic receptors, regulate lipid homeostasis will help to develop preventive and therapeutic approaches. This review describes recent advances in our understanding the atypical roles of three xenobiotic receptors: aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), in metabolic disorders, with a particular focus on their effects on lipid and glucose metabolism. Collectively, the literatures suggest the potential values of AhR, PXR and CAR as therapeutic targets for the treatment of NAFLD, NASH, obesity and diabetes, and cardiovascular diseases.
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Affiliation(s)
- Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peipei Lu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
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Sayed TS, Maayah ZH, Zeidan HA, Agouni A, Korashy HM. Insight into the physiological and pathological roles of the aryl hydrocarbon receptor pathway in glucose homeostasis, insulin resistance, and diabetes development. Cell Mol Biol Lett 2022; 27:103. [PMID: 36418969 PMCID: PMC9682773 DOI: 10.1186/s11658-022-00397-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/25/2022] [Indexed: 11/24/2022] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor that mediates the toxicities of several environmental pollutants. Decades of research have been carried out to understand the role of AhR as a novel mechanism for disease development. Its involvement in the pathogenesis of cancer, cardiovascular diseases, rheumatoid arthritis, and systemic lupus erythematosus have long been known. One of the current hot research topics is investigating the role of AhR activation by environmental pollutants on glucose homeostasis and insulin secretion, and hence the pathogenesis of diabetes mellitus. To date, epidemiological studies have suggested that persistent exposure to environmental contaminants such as dioxins, with subsequent AhR activation increases the risk of specific comorbidities such as obesity and diabetes. The importance of AhR signaling in various molecular pathways highlights that the role of this receptor is far beyond just xenobiotic metabolism. The present review aims at providing significant insight into the physiological and pathological role of AhR and its regulated enzymes, such as cytochrome P450 1A1 (CYP1A1) and CYP1B1 in both types of diabetes. It also provides a comprehensive summary of the current findings of recent research studies investigating the role of the AhR/CYP1A1 pathway in insulin secretion and glucose hemostasis in the pancreas, liver, and adipose tissues. This review further highlights the molecular mechanisms involved, such as gluconeogenesis, hypoxia-inducible factor (HIF), oxidative stress, and inflammation.
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Affiliation(s)
- Tahseen S. Sayed
- grid.412603.20000 0004 0634 1084Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, 2713, Doha, Qatar
| | - Zaid H. Maayah
- grid.412603.20000 0004 0634 1084Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, 2713, Doha, Qatar
| | - Heba A. Zeidan
- grid.498552.70000 0004 0409 8340American School of Doha, Doha, Qatar
| | - Abdelali Agouni
- grid.412603.20000 0004 0634 1084Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, 2713, Doha, Qatar
| | - Hesham M. Korashy
- grid.412603.20000 0004 0634 1084Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, 2713, Doha, Qatar
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Effects of Six Weeks of Hypoxia Exposure on Hepatic Fatty Acid Metabolism in ApoE Knockout Mice Fed a High-Fat Diet. LIFE (BASEL, SWITZERLAND) 2022; 12:life12101535. [PMID: 36294970 PMCID: PMC9605121 DOI: 10.3390/life12101535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/08/2022] [Accepted: 09/28/2022] [Indexed: 11/05/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease with a characteristic of abnormal lipid metabolism. In the present study, we employed apolipoprotein E knockout (ApoE KO) mice to investigate the effects of hypoxia exposure on hepatic fatty acid metabolism and to test whether a high-fat diet (HFD) would suppress the beneficial effect caused by hypoxia treatment. ApoE KO mice were fed a HFD for 12 weeks, and then were forwarded into a six-week experiment with four groups: HFD + normoxia, normal diet (ND) + normoxia, HFD + hypoxia exposure (HE), and ND + HE. The C57BL/6J wild type (WT) mice were fed a ND for 18 weeks as the baseline control. The hypoxia exposure was performed in daytime with normobaric hypoxia (11.2% oxygen, 1 h per time, three times per week). Body weight, food and energy intake, plasma lipid profiles, hepatic lipid contents, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and molecular/biochemical makers and regulators of the fatty acid synthesis and oxidation in the liver were measured at the end of interventions. Six weeks of hypoxia exposure decreased plasma triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) contents but did not change hepatic TG and non-esterified fatty acid (NEFA) levels in ApoE KO mice fed a HFD or ND. Furthermore, hypoxia exposure decreased the mRNA expression of Fasn, Scd1, and Srebp-1c significantly in the HFD + HE group compared with those in the HFD + normoxia group; after replacing a HFD with a ND, hypoxia treatment achieved more significant changes in the measured variables. In addition, the protein expression of HIF-1α was increased only in the ND + HE group but not in the HFD + HE group. Even though hypoxia exposure did not affect hepatic TG and NEFA levels, at the genetic level, the intervention had significant effects on hepatic metabolic indices of fatty acid synthesis, especially in the ND + HE group, while HFD suppressed the beneficial effect of hypoxia on hepatic lipid metabolism in male ApoE KO mice. The dietary intervention of shifting HFD to ND could be more effective in reducing hepatic lipid accumulation than hypoxia intervention.
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Ma Z, Wang Y, Quan Y, Wang Z, Liu Y, Ding Z. Maternal obesity alters methylation level of cytosine in CpG island for epigenetic inheritance in fetal umbilical cord blood. Hum Genomics 2022; 16:34. [PMID: 36045397 PMCID: PMC9429776 DOI: 10.1186/s40246-022-00410-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 08/22/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Over the past few decades, global maternal obesity prevalence has rapidly increased. This condition may induce long-lasting pathophysiological effects on either fetal or infant health that could be attributable to unknown unique changes in the umbilical blood composition. METHODS A total of 34 overweight/obese and 32 normal-weight pregnant women were recruited. Fifteen umbilical blood samples including 8 overweight/obese subjects and 7 normal weight women were sequenced using Targeted Bisulfite Sequencing technology to detect the average methylation level of cytosine and identify the differentially methylated region (DMR). GO and KEGG analyses were then employed to perform pathway enrichment analysis of DMR-related genes and promoters. Moreover, the mRNA levels of methylation-related genes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) were characterized in the samples obtained from these two groups. RESULTS Average methylated cytosine levels in both the CpG islands (CGI) and promoter significantly decreased in overweight/obese groups. A total of 1669 DMRs exhibited differences in their DNA methylation status between the overweight/obese and control groups. GO and KEGG analyses revealed that DMR-related genes and promoters were enriched in the metabolism, cancer and cardiomyopathy signaling pathways. Furthermore, the HDACs and DNMTs mRNA levels trended to decline in overweight/obese groups. CONCLUSIONS Decreased methylated cytosine levels in overweight/obese women induce the gene expression activity at a higher level than in the control group. DMRs between these two groups in the fetal blood may contribute to the changes in gene transcription that underlie the increased risk of metabolic disorders, cancers and cardiomyopathy in their offspring.
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Affiliation(s)
- Zhuoyao Ma
- Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, No.280, Chongqing Road (South), Shanghai, 200025, China
| | - Yingjin Wang
- Department of Obstetrics and Gynecology, Shanghai Eighth People's Hospital, Shanghai, 200235, China
| | - Yanmei Quan
- Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, No.280, Chongqing Road (South), Shanghai, 200025, China
| | - Zhijie Wang
- Department of Obstetrics and Gynecology, Shanghai Eighth People's Hospital, Shanghai, 200235, China.
| | - Yue Liu
- Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, No.280, Chongqing Road (South), Shanghai, 200025, China.
| | - Zhide Ding
- Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, No.280, Chongqing Road (South), Shanghai, 200025, China.
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Deletion of RNF186 expression suppresses diet-induced hepatic steatosis by regulating insulin activity. iScience 2022; 25:103859. [PMID: 35198905 PMCID: PMC8850801 DOI: 10.1016/j.isci.2022.103859] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/17/2021] [Accepted: 01/27/2022] [Indexed: 11/20/2022] Open
Abstract
RING finger protein186 (RNF186) is dramatically upregulated in steatotic livers. The physiological role of RNF186 in non-alcoholic fatty liver disease (NAFLD) remains obscure. Here, we found that hepatocyte-specific RNF186 knockout (RNF186LKO) mice were protected from HFD-induced obesity. RNF186 ablation in liver suppressed inflammatory responses and ER stress and alleviated insulin tolerance, leading to improved glucose and lipid metabolism under HFD conditions. RNA-seq and western blot analyses revealed a significant downregulation of peroxisome proliferator-activated receptor γ, stearoyl-CoA desaturase 1, and cluster of differentiation 36 in the liver of RNF186 knockout mice consuming HFD. RNF186 deletion in liver results in less weight gain during HFD feeding and is associated with reduced liver fat, inflammation, and improved glucose and insulin tolerance. In contrast, upregulation of RNF186 in C57BL/6J mice livers impaired lipid metabolism and insulin tolerance. The collective results suggest that RNF186 may be a potential regulator of NAFLD in obesity.
RNF186 deficiency on high-fat diet alleviates liver steatosis and insulin tolerance RNF186 increased hepatic TG accumulation and impaired insulin sensitivity RNF186 ablation suppresses hepatic inflammation associated with high-fat diet RNF186 maybe a potential regulator of NAFLD in obesity
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Vanderhaeghen T, Timmermans S, Watts D, Paakinaho V, Eggermont M, Vandewalle J, Wallaeys C, Van Wyngene L, Van Looveren K, Nuyttens L, Dewaele S, Vanden Berghe J, Lemeire K, De Backer J, Dirkx L, Vanden Berghe W, Caljon G, Ghesquière B, De Bosscher K, Wielockx B, Palvimo JJ, Beyaert R, Libert C. Reprogramming of glucocorticoid receptor function by hypoxia. EMBO Rep 2022; 23:e53083. [PMID: 34699114 PMCID: PMC8728616 DOI: 10.15252/embr.202153083] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 09/29/2021] [Accepted: 10/05/2021] [Indexed: 01/07/2023] Open
Abstract
Here, we investigate the impact of hypoxia on the hepatic response of glucocorticoid receptor (GR) to dexamethasone (DEX) in mice via RNA-sequencing. Hypoxia causes three types of reprogramming of GR: (i) much weaker induction of classical GR-responsive genes by DEX in hypoxia, (ii) a number of genes is induced by DEX specifically in hypoxia, and (iii) hypoxia induces a group of genes via activation of the hypothalamic-pituitary-adrenal (HPA) axis. Transcriptional profiles are reflected by changed GR DNA-binding as measured by ChIP sequencing. The HPA axis is induced by hypothalamic HIF1α and HIF2α activation and leads to GR-dependent lipolysis and ketogenesis. Acute inflammation, induced by lipopolysaccharide, is prevented by DEX in normoxia but not during hypoxia, and this is attributed to HPA axis activation by hypoxia. We unfold new physiological pathways that have consequences for patients suffering from GC resistance.
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Antenatal corticosteroid therapy modulates hepatic AMPK phosphorylation and maternal lipid metabolism in early lactating rats. Biomed Pharmacother 2021; 144:112355. [PMID: 34794232 DOI: 10.1016/j.biopha.2021.112355] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/07/2021] [Accepted: 10/19/2021] [Indexed: 02/01/2023] Open
Abstract
Antenatal corticosteroid therapy is used to reduce neonatal mortality in preterm infants but it is currently unknown whether this intervention affects lipid metabolism at the peripartum. This study aimed to evaluate if antenatal corticosteroid therapy in pregnant rats and women affects lipid metabolism during early lactation. We evaluated women at risk of preterm delivery that received corticosteroid therapy (CASE) and women that were not exposed to corticosteroid and were not at risk of preterm delivery (CONTROL). Samples were collected to measure serum and milk triacylglycerol (TAG) three days after delivery. Rats were treated with dexamethasone (DEX) between the 15th and the 20th days of pregnancy. Samples were collected at different days after delivery (L3, L8 and L14). TAG was measured in serum, liver and mammary gland (MG). TAG appearance rates were measured after tyloxapol injection and gavage with olive oil. We also evaluated the expression of key genes related to lipid metabolism in the liver and in the MG and hepatic phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC). CASE volunteers delivered earlier than CONTROL but presented unaltered milk and serum TAG concentrations. Early lactating DEX rats exhibited increased TAG in serum, MG and milk. No changes in CD36 and LPL were detected in the MG and liver. Early lactating DEX rats displayed increased TAG appearance rate and reduced hepatic AMPK/ACC phosphorylation. Our data revealed that antenatal corticosteroid therapy reduces hepatic AMPK/ACC phosphorylation during early lactation that reflects in increased TAG concentration in serum, MG and milk.
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Xu L, Song H, Qiu Q, Jiang T, Ge P, Su Z, Ma W, Zhang R, Huang C, Li S, Lin D, Zhang J. Different Expressions of HIF-1α and Metabolism in Brain and Major Visceral Organs of Acute Hypoxic Mice. Int J Mol Sci 2021; 22:6705. [PMID: 34201416 PMCID: PMC8268807 DOI: 10.3390/ijms22136705] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/27/2021] [Accepted: 05/25/2021] [Indexed: 12/18/2022] Open
Abstract
Hypoxia is associated with clinical diseases. Extreme hypoxia leads to multiple organs failure. However, the different effects of hypoxia on brain and visceral organs still need to be clarified, and moreover, characteristics in vulnerable organs suffering from hypoxia remain elusive. In the present study, we first aimed to figure out the hypoxic sensitivity of organs. Adult male mice were exposed to 6% O2 or 8% O2 for 6 h. Control mice were raised under normoxic conditions. In vivo and in vitro imaging of anti-HIF-1α-NMs-cy5.5 nanocomposites showed that the expression level of hypoxia-inducible factor (HIF-1α) was the highest in the liver, followed by kidney and brain. HIF-1α was detected in the hepatocytes of liver, distal convoluted tubules of kidney and neurons of cerebral cortex. The liver, kidney and brain showed distinct metabolic profiles but an identical change in glutamate. Compared with kidney and brain, the liver had more characteristic metabolites and more disturbed metabolic pathways related to glutaminolysis and glycolysis. The level of O-phosphocholine, GTP, NAD and aspartate were upregulated in hypoxic mice brain, which displayed significant positive correlations with the locomotor activity in control mice, but not in hypoxic mice with impaired locomotor activities. Taken together, the liver, kidney and brain are the three main organs of the body that are strongly respond to acute hypoxia, and the liver exhibited the highest hypoxic sensitivity. The metabolic disorders appear to underlie the physiological function changes.
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Affiliation(s)
- Lu Xu
- Institute of Brain Diseases and Cognition, Medical College of Xiamen University, Xiamen 361102, China; (L.X.); (Q.Q.); (W.M.); (R.Z.)
| | - Hua Song
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; (H.S.); (P.G.); (Z.S.)
| | - Qi Qiu
- Institute of Brain Diseases and Cognition, Medical College of Xiamen University, Xiamen 361102, China; (L.X.); (Q.Q.); (W.M.); (R.Z.)
| | - Ting Jiang
- Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China;
| | - Pingyun Ge
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; (H.S.); (P.G.); (Z.S.)
| | - Zaiji Su
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; (H.S.); (P.G.); (Z.S.)
| | - Wenhui Ma
- Institute of Brain Diseases and Cognition, Medical College of Xiamen University, Xiamen 361102, China; (L.X.); (Q.Q.); (W.M.); (R.Z.)
| | - Ran Zhang
- Institute of Brain Diseases and Cognition, Medical College of Xiamen University, Xiamen 361102, China; (L.X.); (Q.Q.); (W.M.); (R.Z.)
| | - Caihua Huang
- Research and Communication Center of Exercise and Health, Xiamen University of Technology, Xiamen 361024, China;
| | - Shanhua Li
- Institute of Brain Diseases and Cognition, Medical College of Xiamen University, Xiamen 361102, China; (L.X.); (Q.Q.); (W.M.); (R.Z.)
| | - Donghai Lin
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; (H.S.); (P.G.); (Z.S.)
| | - Jiaxing Zhang
- Institute of Brain Diseases and Cognition, Medical College of Xiamen University, Xiamen 361102, China; (L.X.); (Q.Q.); (W.M.); (R.Z.)
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14
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Wang L, Liu M, Wu Y, Li X, Yin F, Yin L, Liu J. Free fatty acids induce the demethylation of the fructose 1,6-biphosphatase 2 gene promoter and potentiate its expression in hepatocytes. Food Funct 2021; 12:4165-4175. [PMID: 33977939 DOI: 10.1039/d0fo02654a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Obesity is a serious health issue as it is a social burden and the main risk factor for other metabolic diseases. Increasing evidence indicates that a high-fat diet (HFD) is the key factor for the development of obesity, but the key genes and their associated molecular mechanisms are still not fully understood. In this study, we performed integrated bioinformatic analysis and identified that fructose-1,6 biphosphatase 2 (FBP2) was involved in free fatty acids (FFAs)-induced lipid droplet accumulation in hepatocytes and HFD-induced obesity in mice. Our data showed that palmitate (PA) and oleic acid (OA) induced the expression of FBP2 in time- and dose-dependent manners, and accelerated the development of lipid droplets in LO2 human normal liver cells. In HFD-fed C57BL/6 mice, accompanied by insulin resistance and lipid droplet accumulation, the mRNA and protein levels of FBP2 in the livers also increased significantly. The results from the methylation sequencing PCR (MSP) and bisulfite specific PCR (BSP) indicated that PA/OA induced the demethylation of the FBP2 gene promoter in LO2 cells. Moreover, betaine, a methyl donor, attenuated the expression of the FBP2 gene, the accumulation of lipid droplets, and the expression of perilipin-2, a biomarker of lipid droplets, in LO2 cells. All these findings revealed that FBP2 might be involved in HFD-induced obesity, and it is of interest to investigate the role of FBP2 in the treatment and prevention of obesity and its associated complications.
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Affiliation(s)
- Lujing Wang
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Min Liu
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Yucui Wu
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Xingan Li
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Fei Yin
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Li Yin
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Jianhui Liu
- Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China. and College of Pharmacy& Bioengineering, Chongqing University of Technology, Chongqing 400054, China
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15
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FXR in liver physiology: Multiple faces to regulate liver metabolism. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166133. [PMID: 33771667 DOI: 10.1016/j.bbadis.2021.166133] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/11/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022]
Abstract
The liver is the central metabolic hub which coordinates nutritional inputs and metabolic outputs. Food intake releases bile acids which can be sensed by the bile acid receptor FXR in the liver and the intestine. Hepatic and intestinal FXR coordinately regulate postprandial nutrient disposal in a network of interacting metabolic nuclear receptors. In this review we summarize and update the "classical roles" of FXR as a central integrator of the feeding state response, which orchestrates the metabolic processing of carbohydrates, lipids, proteins and bile acids. We also discuss more recent and less well studied FXR effects on amino acid, protein metabolism, autophagic turnover and inflammation. In addition, we summarize the recent understanding of how FXR signaling is affected by posttranslational modifications and by different FXR isoforms. These modifications and variations in FXR signaling might be considered when FXR is targeted pharmaceutically in clinical applications.
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16
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Kumar A, Sundaram K, Mu J, Dryden GW, Sriwastva MK, Lei C, Zhang L, Qiu X, Xu F, Yan J, Zhang X, Park JW, Merchant ML, Bohler HCL, Wang B, Zhang S, Qin C, Xu Z, Han X, McClain CJ, Teng Y, Zhang HG. High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance. Nat Commun 2021; 12:213. [PMID: 33431899 PMCID: PMC7801461 DOI: 10.1038/s41467-020-20500-w] [Citation(s) in RCA: 163] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 11/30/2020] [Indexed: 12/15/2022] Open
Abstract
High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.
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Affiliation(s)
- Anil Kumar
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
| | - Kumaran Sundaram
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
| | - Jingyao Mu
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
| | - Gerald W Dryden
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
- Department of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Mukesh K Sriwastva
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
| | - Chao Lei
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
| | - Lifeng Zhang
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
| | - Xiaolan Qiu
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
| | - Fangyi Xu
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
| | - Jun Yan
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA
| | - Xiang Zhang
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA
| | - Juw Won Park
- Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY, 40202, USA
- KBRIN Bioinformatics Core, University of Louisville, Louisville, KY, 40202, USA
| | - Michael L Merchant
- Kidney Disease Program and Clinical Proteomics Center, University of Louisville, Louisville, KY, USA
| | - Henry C L Bohler
- Department of Reproductive Endocrinology and Infertility, University of Louisville, Louisville, KY40202, USA
| | - Baomei Wang
- Department of Dermatology, University of Pennsylvania, Philadelphia, 19104, USA
| | - Shuangqin Zhang
- Peeples Cancer Institute, 215 Memorial Drive, Dalton, GA, 30720, USA
| | - Chao Qin
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA
| | - Ziying Xu
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA
| | - Xianlin Han
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA
| | - Craig J McClain
- Department of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Yun Teng
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA.
| | - Huang-Ge Zhang
- James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA.
- Robley Rex Veterans Affairs Medical Center, Louisville, KY, 40206, USA.
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17
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Wan X, He X, Liu Q, Wang X, Ding X, Li H. Frequent and mild scrotal heat stress in mice epigenetically alters glucose metabolism in the male offspring. Am J Physiol Endocrinol Metab 2020; 319:E291-E304. [PMID: 32603600 DOI: 10.1152/ajpendo.00038.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Several studies have reported that health problems occur in assisted reproductive technology (ART)-conceived offspring. Recently, investigations have demonstrated that paternal environmental conditions influence offspring health. However, it is unclear whether the factors that cause male infertility per se affect offspring health and contribute to health problems in ART-born children. Scrotal heat stress represents a common cause for oligoasthenozoospermia, and in these cases, in vitro fertilization-embryo transfer (IVF-ET) is typically recommended for those individuals trying to conceive. We exposed C57BL/6J male mice to frequent and mild scrotal heat stress (fmSHS) (39°C for 30 min once weekly for 5 consecutive wk). Sperm was subjected to IVF-ET with oocytes of untreated C57BL/6J females to produce offspring mice. Glucose intolerance and insulin resistance was observed in the male offspring mice derived from fmSHS-exposed fathers. Islets, after evaluation, remained unchanged. Genes involved in glucose metabolism, especially, those in insulin signaling pathways, showed dysregulation in the liver of the fmSHS-derived male offspring. Differentially methylated regions were found in the sperm of fmSHS-exposed mice by whole genome bisulfite sequencing. Interestingly, abnormal methylation of some genes with altered expression in offspring was observed in both the sperm of fmSHS fathers and the liver of their male offspring. Our results suggest that the factors that cause male infertility can affect male offspring health by an epigenetic mechanism.
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Affiliation(s)
- Xiaoyan Wan
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xiaomei He
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qian Liu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xiaotong Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xiaofang Ding
- Centre of Reproductive Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Honggang Li
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
- Wuhan Tongji Reproductive Medicine Hospital, Jiangan District, Wuhan, People's Republic of China
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18
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Identification and Functional Annotation of Genes Related to Horses' Performance: From GWAS to Post-GWAS. Animals (Basel) 2020; 10:ani10071173. [PMID: 32664293 PMCID: PMC7401650 DOI: 10.3390/ani10071173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/06/2020] [Accepted: 07/08/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary It is assumed that the athletic performance of horses is influenced by a large number of genes; however, to date, not many genomic studies have been performed to identify candidate genes. In this study we performed a systematic review of genome-wide association studies followed by functional analyses aiming to identify the most candidate genes for horse performance. We were successful in identifying 669 candidate genes, from which we built biological process networks. Regulatory elements (transcription factors, TFs) of these genes were identified and used to build a gene–TF network. Genes and TFs presented in this study are suggested to play a role in the studied traits through biological processes related with exercise performance, for example, positive regulation of glucose metabolism, regulation of vascular endothelial growth factor production, skeletal system development, cellular response to fatty acids and cellular response to lipids. In general, this study may provide insights into the genetic architecture underlying horse performance in different breeds around the world. Abstract Integration of genomic data with gene network analysis can be a relevant strategy for unraveling genetic mechanisms. It can be used to explore shared biological processes between genes, as well as highlighting transcription factors (TFs) related to phenotypes of interest. Unlike other species, gene–TF network analyses have not yet been well applied to horse traits. We aimed to (1) identify candidate genes associated with horse performance via systematic review, and (2) build biological processes and gene–TF networks from the identified genes aiming to highlight the most candidate genes for horse performance. Our systematic review considered peer-reviewed articles using 20 combinations of keywords. Nine articles were selected and placed into groups for functional analysis via gene networks. A total of 669 candidate genes were identified. From that, gene networks of biological processes from each group were constructed, highlighting processes associated with horse performance (e.g., regulation of systemic arterial blood pressure by vasopressin and regulation of actin polymerization and depolymerization). Transcription factors associated with candidate genes were also identified. Based on their biological processes and evidence from the literature, we identified the main TFs related to horse performance traits, which allowed us to construct a gene–TF network highlighting TFs and the most candidate genes for horse performance.
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19
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Scott C, Stokes R, Cha KM, Clouston A, Eslam M, Metwally M, Swarbrick MM, George J, Gunton JE. Myeloid cell deletion of Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) induces non-alcoholic steatohepatitis. PLoS One 2019; 14:e0225332. [PMID: 31800592 PMCID: PMC6892561 DOI: 10.1371/journal.pone.0225332] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 11/01/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIM Non-alcoholic steatohepatitis (NASH) is predicted to become the most common cause of cirrhosis and liver failure. Risk factors include obesity, insulin resistance and diabetes. Macrophages and other myeloid cells play crucial roles in initiating and driving inflammation. Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) is a transcription factor which binds to a range of partners to mediate responses to environmental signals, including the diet. In people with diabetes it is decreased in liver. We hypothesised that myeloid cell ARNT activity may contribute to the development of liver pathology. METHODS Floxed-ARNT mice were bred with LysM-Cre mice to generate mice with reduced ARNT in myeloid cells. Animals were fed a high fat diet (HFD) and liver pathology was assessed. Histology, mRNA, fat accumulation and metabolism were studied. RESULTS Animals with reduced myeloid ARNT developed steatohepatitis on a HFD, with additional alterations of metabolism and fat deposition. Steatohepatitis was accompanied by hepatic macrophage infiltration and expression of both M1 and M2 markers. Expression of mRNAs for Cxcl1, Mcp-1, Tnf-α and Tgf-β1 were increased. Human livers from controls and people with NASH were tested; ARNT mRNA was decreased by 80% (p = 0.0004). CONCLUSIONS Decreased myeloid ARNT may play a role in the conversion from non-alcoholic fatty liver to steatohepatitis. Increasing ARNT may be a therapeutic strategy to reduce NASH.
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Affiliation(s)
- Christopher Scott
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Rebecca Stokes
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Kuan Minn Cha
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Andrew Clouston
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Mohammed Eslam
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Mayda Metwally
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Michael M. Swarbrick
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Jacob George
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Jenny E. Gunton
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St. Vincent’s Clinical School, University of NSW, Sydney, NSW, Australia
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20
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Liver Zonation in Health and Disease: Hypoxia and Hypoxia-Inducible Transcription Factors as Concert Masters. Int J Mol Sci 2019; 20:ijms20092347. [PMID: 31083568 PMCID: PMC6540308 DOI: 10.3390/ijms20092347] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 05/06/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
The liver and its zonation contribute to whole body homeostasis. Acute and chronic, not always liver, diseases impair proper metabolic zonation. Various underlying pathways, such as β-catenin, hedgehog signaling, and the Hippo pathway, along with the physiologically occurring oxygen gradient, appear to be contributors. Interestingly, hypoxia and hypoxia-inducible transcription factors can orchestrate those pathways. In the current review, we connect novel findings of liver zonation in health and disease and provide a view about the dynamic interplay between these different pathways and cell-types to drive liver zonation and systemic homeostasis.
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21
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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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22
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Gaspar JM, Velloso LA. Hypoxia Inducible Factor as a Central Regulator of Metabolism - Implications for the Development of Obesity. Front Neurosci 2018; 12:813. [PMID: 30443205 PMCID: PMC6221908 DOI: 10.3389/fnins.2018.00813] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 10/18/2018] [Indexed: 12/19/2022] Open
Abstract
The hypothalamus plays a major role in the regulation of food intake and energy expenditure. In the last decade, it was demonstrated that consumption of high-fat diets triggers the activation of an inflammatory process in the hypothalamus, inducing neurofunctional alterations and contributing to the development of obesity. Hypoxia-inducible factors (HIFs) are key molecules that regulate cellular responses to inflammation and hypoxia, being essential for the normal cell function and survival. Currently, evidence points to a role of HIF pathway in metabolic regulation that could also be involved in the progression of obesity and metabolic diseases. The challenge is to understand how HIF modulation impacts body mass gain and metabolic disorders such as insulin resistance. Distinct animal models with tissue-specific knocking-out or overexpression of hypoxia signaling pathway genes revealed a cell-specificity in the activation of HIF pathways, and some of them have opposite phenotypes among the various HIFs gain- and loss-of-function mouse models. In this review, we discuss the major findings that provide support for a role of HIF pathway involvement in the regulation of metabolism, especially in glucose and energy homeostasis.
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Affiliation(s)
- Joana M Gaspar
- Post-Graduation in Biochemistry, Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Brazil.,Laboratório de Bioenergética e Estresse Oxidativo, Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Lício A Velloso
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil.,National Institute of Science and Technology on Neuroimmunomodulation, Rio de Janeiro, Brazil
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23
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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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HIF-1-dependent lipin1 induction prevents excessive lipid accumulation in choline-deficient diet-induced fatty liver. Sci Rep 2018; 8:14230. [PMID: 30242180 PMCID: PMC6155071 DOI: 10.1038/s41598-018-32586-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 09/11/2018] [Indexed: 02/06/2023] Open
Abstract
Adaptive responses to hypoxia regulate hepatic lipid metabolism, but their consequences in nonalcoholic fatty liver disease (NAFLD) are largely unknown. Here, we show that hypoxia inducible factor-1 (HIF-1), a key determinant of hypoxic adaptations, prevents excessive hepatic lipid accumulation in the progression of NAFLD. When exposed to a choline-deficient diet (CDD) for 4 weeks, the loss of hepatic Hif-1α gene accelerated liver steatosis with enhanced triglyceride accumulation in the liver compared to wild-type (WT) livers. Expression of genes involved in peroxisomal fatty acid oxidation was suppressed significantly in CDD-treated WT livers, whereas this reduction was further enhanced in Hif-1α-deficient livers. A lack of induction and nuclear accumulation of lipin1, a key regulator of the PPARα/PGC-1α pathway, could be attributed to impaired peroxisomal β-oxidation in Hif-1α-deficient livers. The lipin1-mediated binding of PPARα to the acyl CoA oxidase promoter was markedly reduced in Hif-1α-deficient mice exposed to a CDD. Moreover, forced Lipin1 expression restored the aberrant lipid accumulation caused by Hif-1α deletion in cells incubated in a choline-deficient medium. These results strongly suggest that HIF-1 plays a crucial role in the regulation of peroxisomal lipid metabolism by activating the expression and nuclear accumulation of lipin1 in NAFLD.
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De Jesus A, Chang HC, Ardehali H. Metabolic Suppression of HIF-1α Contributes to Susceptibility of Ischemic Injury in Diabetic Hearts. JACC Basic Transl Sci 2018; 3:499-502. [PMID: 30175273 PMCID: PMC6116327 DOI: 10.1016/j.jacbts.2018.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
| | | | - Hossein Ardehali
- Feinberg Cardiovascular Research Institute (FCVRI), Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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Liao X, Song L, Zhang L, Wang H, Tong Q, Xu J, Yang G, Yang S, Zheng H. LAMP3 regulates hepatic lipid metabolism through activating PI3K/Akt pathway. Mol Cell Endocrinol 2018; 470:160-167. [PMID: 29056532 DOI: 10.1016/j.mce.2017.10.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 09/11/2017] [Accepted: 10/16/2017] [Indexed: 02/06/2023]
Abstract
Lysosome associated membrane protein 3 (LAMP3), a highly glycosylated protein, is one member of the LAMPs family. LAMPs family plays a critical role in the autolysosome fusion process. Autophagy was recently confirmed to regulate hepatic lipolysis. However, the physiological function of LAMP3 in lipid metabolism is not clear. In the current study, we discovered that the LAMP3 expression level was higher in the liver tissues of non-alcoholic fatty liver disease (NAFLD) patients and high-fat diet and ob/ob mice than in the matched control groups. LAMP3 expression was also obviously increased in hepatocellular carcinoma (HCC) cells treated with free fatty acids. Moreover, marked accumulation of intracellular lipid droplets and triglycerides (TG) was observed after LAMP3 overexpression in HCC cells. Further study showed that LAMP3 overexpression activated Akt and upregulated the expression of the lipogenic enzymes FASN and SCD-1 in HepG2 cells. Additionally, the increased TG content induced by LAMP3 overexpression was attenuated by treatment with a PI3K/Akt pathway inhibitor. Our findings demonstrated that LAMP3 is an important regulator of hepatic lipid metabolism, which provides a line of evidence for taking LAMP3 as a drug target in lipid metabolism disorder-associated diseases, such as NAFLD and obesity.
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Affiliation(s)
- Xiaoyu Liao
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Lingyu Song
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Linlin Zhang
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Hui Wang
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qiang Tong
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jing Xu
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Gangyi Yang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
| | - Hongting Zheng
- Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
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Revilla M, Puig-Oliveras A, Crespo-Piazuelo D, Criado-Mesas L, Castelló A, Fernández AI, Ballester M, Folch JM. Expression analysis of candidate genes for fatty acid composition in adipose tissue and identification of regulatory regions. Sci Rep 2018; 8:2045. [PMID: 29391556 PMCID: PMC5794915 DOI: 10.1038/s41598-018-20473-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 01/16/2018] [Indexed: 02/07/2023] Open
Abstract
The aim of this work was to study the genetic basis of the backfat expression of lipid-related genes associated with meat quality traits in pigs. We performed a genome-wide association study with the backfat gene expression measured in 44 genes by qPCR and the PorcineSNP60 BeadChip genotypes in 115 Iberian x Landrace backcross animals. A total of 193 expression-associated SNPs located in 19 chromosomal regions were associated with expression levels of ACSM5, ELOVL6, FABP4, FADS2, and SLC27A4 genes. Three expression quantitative trail loci (eQTLs) corresponding to ACSM5, FABP4, and FADS2 were classified as cis-acting eQTLs, whereas the remaining 16 eQTLs have trans-regulatory effects. Remarkably, a SNP in the ACSM5 promoter region and a SNP in the 3′UTR region of FABP4 were the most associated polymorphisms with the ACSM5 and FABP4 expression levels, respectively. Moreover, relevant lipid-related genes mapped in the trans-eQTLs regions associated with the ACSM5, FABP4, FADS2, and SLC27A4 genes. Interestingly, a trans-eQTL hotspot on SSC13 regulating the gene expression of ELOVL6, ELOLV5, and SCD, three important genes implicated in the elongation and desaturation of fatty acids, was identified. These findings provide new data to further understand the functional regulatory mechanisms implicated in the variation of fatty acid composition in pigs.
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Affiliation(s)
- Manuel Revilla
- Animal Genomics Department, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus UAB, 08193, Bellaterra, Spain. .,Departament de Ciència Animal i dels Aliments, Facultat de Veterinària, Universitat Autònoma de Barcelona (UAB), 08193, Bellaterra, Spain.
| | - Anna Puig-Oliveras
- Animal Genomics Department, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus UAB, 08193, Bellaterra, Spain.,Departament de Ciència Animal i dels Aliments, Facultat de Veterinària, Universitat Autònoma de Barcelona (UAB), 08193, Bellaterra, Spain
| | - Daniel Crespo-Piazuelo
- Animal Genomics Department, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus UAB, 08193, Bellaterra, Spain.,Departament de Ciència Animal i dels Aliments, Facultat de Veterinària, Universitat Autònoma de Barcelona (UAB), 08193, Bellaterra, Spain
| | - Lourdes Criado-Mesas
- Animal Genomics Department, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus UAB, 08193, Bellaterra, Spain.,Departament de Ciència Animal i dels Aliments, Facultat de Veterinària, Universitat Autònoma de Barcelona (UAB), 08193, Bellaterra, Spain
| | - Anna Castelló
- Animal Genomics Department, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus UAB, 08193, Bellaterra, Spain.,Departament de Ciència Animal i dels Aliments, Facultat de Veterinària, Universitat Autònoma de Barcelona (UAB), 08193, Bellaterra, Spain
| | - Ana I Fernández
- Departamento de Genética Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), 28040, Madrid, Spain
| | - Maria Ballester
- Departament de Genètica i Millora Animal, Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Torre Marimon, 08140, Caldes de Montbui, Spain
| | - Josep M Folch
- Animal Genomics Department, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus UAB, 08193, Bellaterra, Spain.,Departament de Ciència Animal i dels Aliments, Facultat de Veterinària, Universitat Autònoma de Barcelona (UAB), 08193, Bellaterra, Spain
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Scott CH, Cha KM, Ngai J, Jiang C, Cheng K, Stokes RA, Ho KWK, George J, Gonzalez FJ, Gunton JE. Hepatic Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) regulates metabolism in mice. PLoS One 2017; 12:e0186543. [PMID: 29190746 PMCID: PMC5708799 DOI: 10.1371/journal.pone.0186543] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 09/11/2017] [Indexed: 01/09/2023] Open
Abstract
Background & aims Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) and its partners hypoxia-inducible factors (HIF)-1α and HIF-2α are candidate factors for the well-known link between the liver, metabolic dysfunction and elevation in circulating lipids and glucose. Methods: Hepatocyte-specific ARNT-null (LARNT), HIF-1α-null (LHIF1α) and HIF-2α-null (LHIF2α) mice were created. Results LARNT mice had increased fasting glucose, impaired glucose tolerance, increased glucose production, raised post-prandial serum triglycerides (TG) and markedly lower hepatic ATP versus littermate controls. There was increased expression of G6Pase, Chrebp, Fas and Scd-1 mRNAs in LARNT animals. Surprisingly, LHIF1α and LHIF2α mice exhibited no alterations in any metabolic parameter assessed. Conclusions These results provide convincing evidence that reduced hepatic ARNT can contribute to inappropriate hepatic glucose production and post-prandial dyslipidaemia. Hepatic ARNT may be a novel therapeutic target for improving post-prandial hypertriglyceridemia and glucose homeostasis.
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Affiliation(s)
- Christopher H. Scott
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW. Australia
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Kuan-Minn Cha
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW. Australia
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Jason Ngai
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Changtao Jiang
- Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Kim Cheng
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW. Australia
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Rebecca A. Stokes
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW. Australia
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Kenneth W. K. Ho
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Jacob George
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW. Australia
- Storr Liver Unit, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW. Australia
| | - Frank J. Gonzalez
- Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Jenny E. Gunton
- The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW. Australia
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
- St. Vincent’s Clinical School, University of NSW, Sydney, NSW, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW Australia
- * E-mail:
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Abstract
Endocrine is an important and tightly regulated system for maintaining body homeostasis. Endocrine glands produce hormones, which are released into blood stream to guide the target cells responding to all sorts of stimulations. For maintaining body homeostasis, the secretion and activity of a particular hormone needs to be adjusted in responding to environmental challenges such as changes in nutritional status or chronic stress. Hypoxia, a status caused by reduced oxygen availability or imbalance of oxygen consumption/supply in an organ or within a cell, is a stress that affects many physiological and pathological processes. Hypoxic stress in endocrine organs is especially critical because endocrine glands control body homeostasis. Local hypoxia affects not only the particular gland but also the downstream cells/organs regulated by hormones secreted from this gland. Hypoxia-inducible factors (HIFs) are transcription factors that function as master regulators of oxygen homeostasis. Recent studies report that aberrant expression of HIFs in endocrine organs may result in the development and/or progression of diseases including diabetes, endometriosis, infertility and cancers. In this article, we will review recent findings in HIF-mediated endocrine organ dysfunction and the systemic syndromes caused by these disorders.
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Affiliation(s)
- Hsiu-Chi Lee
- Institute of Basic Medical SciencesCollege of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shaw-Jenq Tsai
- Institute of Basic Medical SciencesCollege of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of PhysiologyCollege of Medicine, National Cheng Kung University, Tainan, Taiwan
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Asai Y, Yamada T, Tsukita S, Takahashi K, Maekawa M, Honma M, Ikeda M, Murakami K, Munakata Y, Shirai Y, Kodama S, Sugisawa T, Chiba Y, Kondo Y, Kaneko K, Uno K, Sawada S, Imai J, Nakamura Y, Yamaguchi H, Tanaka K, Sasano H, Mano N, Ueno Y, Shimosegawa T, Katagiri H. Activation of the Hypoxia Inducible Factor 1α Subunit Pathway in Steatotic Liver Contributes to Formation of Cholesterol Gallstones. Gastroenterology 2017; 152:1521-1535.e8. [PMID: 28088462 DOI: 10.1053/j.gastro.2017.01.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 01/05/2017] [Accepted: 01/05/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Hypoxia-inducible factor 1α subunit (HIF1A) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD increases the risk for cholesterol gallstone disease by unclear mechanisms. We studied the relationship between HIF1A and gallstone formation associated with liver steatosis. METHODS We performed studies with mice with inducible disruption of Hif1a in hepatocytes via a Cre adenoviral vector (inducible hepatocyte-selective HIF1A knockout [iH-HIFKO] mice), and mice without disruption of Hif1a (control mice). Mice were fed a diet rich in cholesterol and cholate for 1 or 2 weeks; gallbladders were collected and the number of gallstones was determined. Livers and biliary tissues were analyzed by histology, quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and immunoblots. We measured concentrations of bile acid, cholesterol, and phospholipid in bile and rates of bile flow. Primary hepatocytes and cholangiocytes were isolated and analyzed. HIF1A was knocked down in Hepa1-6 cells with small interfering RNAs. Liver biopsy samples from patients with NAFLD, with or without gallstones, were analyzed by quantitative reverse-transcription polymerase chain reaction. RESULTS Control mice fed a diet rich in cholesterol and cholate developed liver steatosis with hypoxia; levels of HIF1A protein were increased in hepatocytes around central veins and 90% of mice developed cholesterol gallstones. Only 20% of the iH-HIFKO mice developed cholesterol gallstones. In iH-HIFKO mice, the biliary lipid concentration was reduced by 36%, compared with control mice, and bile flow was increased by 35%. We observed increased water secretion from hepatocytes into bile canaliculi to mediate these effects, resulting in suppression of cholelithogenesis. Hepatic expression of aquaporin 8 (AQP8) protein was 1.5-fold higher in iH-HIFKO mice than in control mice. Under hypoxic conditions, cultured hepatocytes increased expression of Hif1a, Hmox1, and Vegfa messenger RNAs (mRNAs), and down-regulated expression of AQP8 mRNA and protein; AQP8 down-regulation was not observed in cells with knockdown of HIF1A. iH-HIFKO mice had reduced inflammation and mucin deposition in the gallbladder compared with control mice. Liver tissues from patients with NAFLD with gallstones had increased levels of HIF1A, HMOX1, and VEGFA mRNAs, compared with livers from patients with NAFLD without gallstones. CONCLUSIONS In steatotic livers of mice, hypoxia up-regulates expression of HIF1A, which reduces expression of AQP8 and concentrates biliary lipids via suppression of water secretion from hepatocytes. This promotes cholesterol gallstone formation. Livers from patients with NAFLD and gallstones express higher levels of HIF1A than livers from patients with NAFLD without gallstones.
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Affiliation(s)
- Yoichiro Asai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Yamada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Sohei Tsukita
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masamitsu Maekawa
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan
| | - Midori Honma
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masanori Ikeda
- Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Keigo Murakami
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuichiro Munakata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuta Shirai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Sugisawa
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yumiko Chiba
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keizo Kaneko
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kenji Uno
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shojiro Sawada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Nakamura
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroaki Yamaguchi
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan
| | - Kozo Tanaka
- Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Nariyasu Mano
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
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Hepatic Transcriptome Profiles of Mice with Diet-Induced Nonalcoholic Steatohepatitis Treated with Astaxanthin and Vitamin E. Int J Mol Sci 2017; 18:ijms18030593. [PMID: 28282876 PMCID: PMC5372609 DOI: 10.3390/ijms18030593] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 03/04/2017] [Indexed: 02/06/2023] Open
Abstract
Astaxanthin alleviates hepatic lipid accumulation and peroxidation, inflammation, and fibrosis in mice with high-cholesterol, high-cholate, and high-fat (CL) diet-induced nonalcoholic steatohepatitis (NASH). It has been proposed as a potential new treatment to inhibit the progression of NASH in humans. In this study, we compared hepatic gene expression profiles after treatment with astaxanthin or the antioxidant vitamin E in mice with CL diet-induced NASH. Comprehensive gene expression analyses of the livers of mice fed a standard, CL, or CL diet containing astaxanthin or vitamin E for 12 weeks were performed using a DNA microarray. Both astaxanthin and vitamin E effectively improved gene expression associated with eukaryotic initiation factor-2 (EIF2) signaling, which is suppressed in NASH by endoplasmic reticulum (ER) stress in the liver. However, astaxanthin did not improve the expression of genes associated with mitochondrial dysfunction. Astaxanthin, but not vitamin E, was predicted to suppress the actions of ligand-dependent nuclear receptors peroxisome proliferator-activated receptors, (PPAR) α (PPARA) and PPARδ (PPARD), and to affect related molecules. Establishing a new therapy using astaxanthin will require elucidation of astaxanthin’s molecular action on the functions of PPARα and related molecules in the livers of mice with diet-induced NASH.
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Badin PM, Sopariwala DH, Lorca S, Narkar VA. Muscle Arnt/Hif1β Is Dispensable in Myofiber Type Determination, Vascularization and Insulin Sensitivity. PLoS One 2016; 11:e0168457. [PMID: 28005939 PMCID: PMC5178999 DOI: 10.1371/journal.pone.0168457] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 12/01/2016] [Indexed: 02/07/2023] Open
Abstract
Aryl Hydrocarbon Receptor Nuclear Translocator/ hypoxia-inducible factor 1 beta (ARNT/ HIF1β), a member of bHLH-PAS family of transcriptional factors, plays a critical role in metabolic homeostasis, insulin resistance and glucose intolerance. The contributions of ARNT in pancreas, liver and adipose tissue to energy balance through gene regulation have been described. Surprisingly, the impact of ARNT signaling in the skeletal muscles, one of the major organs involved in glucose disposal, has not been investigated, especially in type II diabetes. Here we report that ARNT is expressed in the skeletal muscles, particularly in the energy-efficient oxidative slow-twitch myofibers, which are characterized by increased oxidative capacity, mitochondrial content, vascular supply and insulin sensitivity. However, muscle-specific deletion of ARNT did not change myofiber type distribution, oxidative capacity, mitochondrial content, capillarity, or the expression of genes associated with these features. Consequently, the lack of ARNT in the skeletal muscle did not affect weight gain, lean/fat mass, insulin sensitivity and glucose tolerance in lean mice, nor did it impact insulin resistance and glucose intolerance in high fat diet-induced obesity. Therefore, skeletal muscle ARNT is dispensable for controlling muscle fiber type and metabolic regulation, as well as diet-induced weight control, insulin sensitivity and glucose tolerance.
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Affiliation(s)
- Pierre-Marie Badin
- Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, UTHealth, Houston, TX, United States of America
| | - Danesh H. Sopariwala
- Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, UTHealth, Houston, TX, United States of America
| | - Sabina Lorca
- Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, UTHealth, Houston, TX, United States of America
| | - Vihang A. Narkar
- Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, UTHealth, Houston, TX, United States of America
- Integrative Biology and Pharmacology, McGovern Medical School, UTHealth, Houston, TX, United States of America
- Graduate School of Biomedical Sciences, McGovern Medical School, UTHealth, Houston, TX, United States of America
- * E-mail:
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Lefere S, Van Steenkiste C, Verhelst X, Van Vlierberghe H, Devisscher L, Geerts A. Hypoxia-regulated mechanisms in the pathogenesis of obesity and non-alcoholic fatty liver disease. Cell Mol Life Sci 2016; 73:3419-31. [PMID: 27091156 PMCID: PMC11108443 DOI: 10.1007/s00018-016-2222-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 04/05/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023]
Abstract
The pandemic rise in obesity has resulted in an increased incidence of metabolic complications. Non-alcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome and has become the most common chronic liver disease in large parts of the world. The adipose tissue expansion and hepatic fat accumulation characteristics of these disorders compromise local oxygen homeostasis. The resultant tissue hypoxia induces adaptive responses to restore oxygenation and tissue metabolism and cell survival. Hypoxia-inducible factors (HIFs) function as master regulators of this hypoxia adaptive response, and are in turn hydroxylated by prolyl hydroxylases (PHDs). PHDs are the main cellular oxygen sensors and regulate HIF proteasomal degradation in an oxygen-dependent manner. HIFs and PHDs are implicated in numerous physiological and pathological conditions. Extensive research using genetic models has revealed that hypoxia signaling is also a key mechanism in adipose tissue dysfunction, leading to adipose tissue fibrosis, inflammation and insulin resistance. Moreover, hypoxia affects liver lipid metabolism and deranges hepatic lipid accumulation. This review summarizes the molecular mechanisms through which the hypoxia adaptive response affects adipocyte and hepatic metabolism, and the therapeutic possibilities of modulating HIFs and PHDs in obesity and fatty liver disease.
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Affiliation(s)
- Sander Lefere
- Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium.
| | - Christophe Van Steenkiste
- Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium
- Department of Gastroenterology and Hepatology, Maria Middelares Hospital, Ghent, Belgium
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium
| | - Hans Van Vlierberghe
- Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium
| | - Lindsey Devisscher
- Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium
| | - Anja Geerts
- Department of Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 1K12IE, 9000, Ghent, Belgium
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Cheng YS, Seibert O, Klöting N, Dietrich A, Straßburger K, Fernández-Veledo S, Vendrell JJ, Zorzano A, Blüher M, Herzig S, Berriel Diaz M, Teleman AA. PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis. PLoS Genet 2015; 11:e1005561. [PMID: 26440364 PMCID: PMC4595073 DOI: 10.1371/journal.pgen.1005561] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 09/10/2015] [Indexed: 01/12/2023] Open
Abstract
In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state. After a meal, dietary glucose travels through the hepatic portal vein to the liver. A substantial part of this glucose is taken up by liver, which converts it to glycogen which is stored, and lipids which are in part stored and in part secreted as VLDL particles. The rest of the organs receive whatever glucose the liver leaves in circulation, plus the secreted lipids. Hence the liver plays a crucial role in determining the balance of sugar versus lipids in the body after a meal. This balance is very important, because too much glucose in circulation leads to diabetic complications whereas too much VLDL increases risk of atherosclerosis. Little is known about how the liver strikes this balance. We identify here a phosphatase—the PP2A holoenzyme containing the PPP2R5C regulatory subunit—as a regulator of this process. We find that knockdown of PPP2R5C in mouse liver specifically causes it to uptake elevated levels of glucose, and secrete elevated levels of VLDL into circulation. This leads to a phenotype of improved glucose tolerance and insulin sensitivity. The prediction from these functional studies in mice is that elevated levels of PPP2R5C expression should lead to insulin resistance. Indeed, we find that PPP2R5C expression levels are elevated in diabetic patients, or healthy controls with visceral obesity, raising the possibility that dysregulation of PPP2R5C expression in humans may contribute towards metabolic dysfunction.
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Affiliation(s)
| | - Oksana Seibert
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nora Klöting
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Arne Dietrich
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | | | - Sonia Fernández-Veledo
- Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili. Universitat, Rovira i Virgili, CIBERDEM, Tarragona, Spain
| | - Joan J. Vendrell
- Hospital Universitari de Tarragona Joan XXIII. Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, CIBERDEM, Tarragona, Spain
| | - Antonio Zorzano
- Institute for Research in Biomedicine (IRB Barcelona), Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, and CIBERDEM, Barcelona, , Spain
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Stephan Herzig
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany, and Joint Heidelberg-IDC Translational Diabetes Program, University Hospital Heidelberg, Heidelberg, Germany
- Chair Molecular Metabolic Control, Medical Faculty, Technical University Munich, Germany
| | - Mauricio Berriel Diaz
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany, and Joint Heidelberg-IDC Translational Diabetes Program, University Hospital Heidelberg, Heidelberg, Germany
- * E-mail: (MBD); (AAT)
| | - Aurelio A. Teleman
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- * E-mail: (MBD); (AAT)
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Hogan MF, Ravnskjaer K, Matsumura S, Huising MO, Hull RL, Kahn SE, Montminy M. Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2. J Biol Chem 2015; 290:25997-6006. [PMID: 26342077 DOI: 10.1074/jbc.m115.679266] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Indexed: 11/06/2022] Open
Abstract
Under fasting conditions, increases in circulating concentrations of glucagon maintain glucose homeostasis via the induction of hepatic gluconeogenesis. Triggering of the cAMP pathway in hepatocytes stimulates the gluconeogenic program via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2 and CRTC3. In parallel, decreases in circulating insulin also increase gluconeogenic gene expression via the de-phosphorylation and activation of the forkhead transcription factor FOXO1. Hepatic gluconeogenesis is increased in insulin resistance where it contributes to the attendant hyperglycemia. Whether selective activation of the hepatic CREB/CRTC pathway is sufficient to trigger metabolic changes in other tissues is unclear, however. Modest hepatic expression of a phosphorylation-defective and therefore constitutively active CRTC2S171,275A protein increased gluconeogenic gene expression under fasting as well as feeding conditions. Circulating glucose concentrations were constitutively elevated in CRTC2S171,275A-expressing mice, leading to compensatory increases in circulating insulin concentrations that enhance FOXO1 phosphorylation. Despite accompanying decreases in FOXO1 activity, hepatic gluconeogenic gene expression remained elevated in CRTC2S171,275A mice, demonstrating that chronic increases in CRTC2 activity in the liver are indeed sufficient to promote hepatic insulin resistance and to disrupt glucose homeostasis.
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Affiliation(s)
- Meghan F Hogan
- From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108
| | - Kim Ravnskjaer
- From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Shigenobu Matsumura
- From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo-ku, Kyoto, 606-8502, Japan, and
| | - Mark O Huising
- From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, California 95616
| | - Rebecca L Hull
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108
| | - Steven E Kahn
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108
| | - Marc Montminy
- From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037,
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Squadrone S, Ciccotelli V, Prearo M, Favaro L, Scanzio T, Foglini C, Abete MC. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA): emerging contaminants of increasing concern in fish from Lake Varese, Italy. ENVIRONMENTAL MONITORING AND ASSESSMENT 2015; 187:438. [PMID: 26085281 DOI: 10.1007/s10661-015-4686-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 06/09/2015] [Indexed: 06/04/2023]
Abstract
Perfluoroalkylated substances (PFASs) are highly fluorinated aliphatic compounds with high thermal and chemical stability, used in a range of industrial applications. Extensive screening analyses in biota samples from all over the world have shown the bioaccumulation of PFAS into higher trophic levels in the food chain. Perfluorooctane sulfonic acid (PFOS) and perfluoroctanoic acid (PFOA) are potential reproductive and developmental toxicants and are considered to be emerging endocrine disrupters. Ingestion of fish and other seafood is considered the main source of exposure of these contaminants. Here, we quantified PFOS and PFOA by LC-MS/MS in muscle samples of European perch from Lake Varese, Italy. PFOS was detected in all samples with concentrations of up to 17.2 ng g(-1). Although the reported values were lower than the recommended total daily intake (TDI) proposed by the European Food Safety Authority (EFSA), fish from Lake Varese may be a significant source of dietary PFOS exposure.
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Affiliation(s)
- S Squadrone
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, via Bologna 148, 10154, Torino, Italy,
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Scott C, Cha K, Rao R, Liddle C, George J, Gunton JE. Hepatocyte-specific deletion of ARNT (aryl hydrocarbon Receptor Nuclear Translocator) results in altered fibrotic gene expression in the thioacetamide model of liver injury. PLoS One 2015; 10:e0121650. [PMID: 25812120 PMCID: PMC4374875 DOI: 10.1371/journal.pone.0121650] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Accepted: 01/09/2015] [Indexed: 01/07/2023] Open
Abstract
Background & Aims Recent studies have shown that increased expression of liver hypoxia inducible factor 2-α (HIF-2α) leads to liver inflammation and a pro-fibrotic gene expression signature. Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) is required for HIF-2α transcriptional activity and has previously been shown to regulate hepatic metabolism in mice. In these studies we examined the role of hepatocyte ARNT in the thioacetamide (TAA)-induced model of liver fibrosis. Methods Hepatocyte-specific ARNT-null (LARNT) mice were created using an albumin promoter-driven Cre recombinase. LARNT and floxed control (FC) littermates were placed on chow diet and received twice weekly intraperitoneal injections of 0.15mg/g body weight of TAA for 13 weeks. Results TAA treated LARNT and FC mice had a similar pattern of fibrosis. Quantification of Sirius red histology staining and hydroxyproline content revealed mixed results in terms of collagen deposition in LARNT livers. There was no significant difference in hepatocyte apoptosis or proliferation, as assessed by cleaved Caspase-3 and Ki67 respectively. LARNT mice had decreased macrophage accumulation, and decreased liver mRNA expression of Col1A1, Col1A2, Col5A1, Tgfβ1, Tgfβ2, Timp1 and Timp2. Conclusions Deletion of hepatocyte ARNT leads to altered expression of collagen associated mRNA and reduced macrophage infiltration in the TAA-induced model of liver fibrosis. It appears that hepatocyte ARNT is not a requirement for initiation of liver fibrogenesis, but does regulate pro-fibrotic gene expression and macrophage accumulation.
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Affiliation(s)
- Christopher Scott
- Diabetes, Obesity & Endocrinology Group, Westmead Millennium Institute, Westmead Hospital, Sydney, NSW, Australia
- Faculty of Medicine, University of Sydney, Westmead, Sydney, NSW, Australia
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Kuan Cha
- Diabetes, Obesity & Endocrinology Group, Westmead Millennium Institute, Westmead Hospital, Sydney, NSW, Australia
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Renuka Rao
- The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Sydney, NSW, Australia
| | - Christopher Liddle
- The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Sydney, NSW, Australia
| | - Jacob George
- Faculty of Medicine, University of Sydney, Westmead, Sydney, NSW, Australia
- The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Sydney, NSW, Australia
| | - Jenny E. Gunton
- Diabetes, Obesity & Endocrinology Group, Westmead Millennium Institute, Westmead Hospital, Sydney, NSW, Australia
- Faculty of Medicine, University of Sydney, Westmead, Sydney, NSW, Australia
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
- St. Vincent’s Clinical School, University of NSW, Sydney, NSW, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW Australia
- * E-mail:
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Arai T, Kato Y, Ishimoto K, Kanai M, Shinjo S, Sayama K, Suzuki T, Doi T, Johnson RS, Suematsu M, Goda N. WITHDRAWN: Loss of hepatic HIF-1α accelerates lipid accumulation by inhibiting peroxisomal fatty acid oxidation in nonalcoholic fatty liver disease. J Hepatol 2015:S0168-8278(15)00074-4. [PMID: 25681160 DOI: 10.1016/j.jhep.2015.01.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 01/09/2015] [Accepted: 01/29/2015] [Indexed: 12/04/2022]
Abstract
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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Affiliation(s)
- Takatomo Arai
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo, Japan
| | - Yuki Kato
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo, Japan
| | - Kenji Ishimoto
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Mai Kanai
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo, Japan
| | - Satoko Shinjo
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo, Japan
| | - Keimon Sayama
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo, Japan
| | - Tomohiro Suzuki
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo, Japan
| | - Takefumi Doi
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Randall S Johnson
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Makoto Suematsu
- Department of Biochemistry, School of Medicine, Keio University; JST, ERATO, Suematsu Gas Biology Project, Tokyo, Japan
| | - Nobuhito Goda
- Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo, Japan.
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Su EJ, Xin H, Yin P, Dyson M, Coon J, Farrow KN, Mestan KK, Ernst LM. Impaired fetoplacental angiogenesis in growth-restricted fetuses with abnormal umbilical artery doppler velocimetry is mediated by aryl hydrocarbon receptor nuclear translocator (ARNT). J Clin Endocrinol Metab 2015; 100:E30-40. [PMID: 25343232 PMCID: PMC4283004 DOI: 10.1210/jc.2014-2385] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
CONTEXT Fetal growth restriction with abnormal umbilical artery Doppler velocimetry (FGRadv), reflective of elevated fetoplacental vascular resistance, is associated with increased risks of fetal morbidity and mortality even in comparison to those of growth-restricted fetuses with normal placental blood flow. One major cause of this abnormally elevated fetoplacental vascular resistance is the aberrantly formed, thin, elongated villous vessels that are seen in FGRadv placentas. OBJECTIVE The purpose of this study was to determine the role of fetoplacental endothelial cells (ECs) in angiogenesis in normal pregnancies and in those complicated by FGRadv. DESIGN AND PARTICIPANTS Human placental specimens were obtained from FGRadv and gestational age-matched, appropriately grown control pregnancies for EC isolation/culture and for immunohistochemical studies. Additional mechanistic studies were performed on ECs isolated from subjects with term, uncomplicated pregnancies. MAIN OUTCOME MEASURES We evaluated tube formation and differential angiogenic gene expression in FGRadv and control ECs, and we used ECs from uncomplicated pregnancies to further elucidate the molecular mechanisms by which angiogenesis is impaired in FGRadv pregnancies. RESULTS Tube formation assays showed that FGRadv ECs demonstrate fewer branch points and total length compared with those from gestational age-matched controls, and this defect was not rescued by exposure to hypoxia. FGRadv ECs also demonstrated lower aryl hydrocarbon receptor nuclear translocator (ARNT) expression. ARNT knockdown resulted in suppression of key angiogenic genes including vascular endothelial growth factor A expression and led to deficient tube formation. CONCLUSIONS ARNT expression in the placental vasculature mediates key angiogenic expression and fetoplacental EC angiogenesis, and low ARNT expression in FGRadv ECs appears to be a key factor in deficient angiogenesis. This, in turn, results in malformed thin villous vessels that structurally contribute to the abnormally elevated fetoplacental vascular resistance that is associated with high morbidity and mortality in fetal growth restriction.
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Affiliation(s)
- Emily J Su
- Department of Obstetrics and Gynecology (E.J.S., H.X., P.Y., M.D., J.C.), Division of Maternal-Fetal Medicine and/or Division of Reproductive Science in Medicine, and Department of Pathology (L.M.E.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; and Department of Pediatrics (K.N.F., K.K.M.), Division of Neonatology, Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois 60611
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Suzuki T, Shinjo S, Arai T, Kanai M, Goda N. Hypoxia and fatty liver. World J Gastroenterol 2014; 20:15087-15097. [PMID: 25386057 PMCID: PMC4223242 DOI: 10.3748/wjg.v20.i41.15087] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 02/14/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.
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Wu R, Chang HC, Khechaduri A, Chawla K, Tran M, Chai X, Wagg C, Ghanefar M, Jiang X, Bayeva M, Gonzalez F, Lopaschuk G, Ardehali H. Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy. J Clin Invest 2014; 124:4795-4806. [PMID: 25329697 PMCID: PMC4347233 DOI: 10.1172/jci76737] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 09/08/2014] [Indexed: 12/20/2022] Open
Abstract
Patients with type 2 diabetes often present with cardiovascular complications; however, it is not clear how diabetes promotes cardiac dysfunction. In murine models, deletion of the gene encoding aryl hydrocarbon nuclear translocator (ARNT, also known as HIF1β) in the liver or pancreas leads to a diabetic phenotype; however, the role of ARNT in cardiac metabolism is unknown. Here, we determined that cardiac-specific deletion of Arnt in adult mice results in rapid development of cardiomyopathy (CM) that is characterized by accumulation of lipid droplets. Compared with hearts from ARNT-expressing mice, ex vivo analysis of ARNT-deficient hearts revealed a 2-fold increase in fatty acid (FA) oxidation as well as a substantial increase in the expression of PPARα and its target genes. Furthermore, deletion of both Arnt and Ppara preserved cardiac function, improved survival, and completely reversed the FA accumulation phenotype, indicating that PPARα mediates the detrimental effects of Arnt deletion in the heart. Finally, we determined that ARNT directly regulates Ppara expression by binding to its promoter and forming a complex with HIF2α. Together, these findings suggest that ARNT is a critical regulator of myocardial FA metabolism and that its deletion leads to CM and an increase in triglyceride accumulation through PPARα.
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Affiliation(s)
- Rongxue Wu
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Hsiang-Chun Chang
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Arineh Khechaduri
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Kusum Chawla
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Minh Tran
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Xiaomeng Chai
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Cory Wagg
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Mohsen Ghanefar
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Xinghang Jiang
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Marina Bayeva
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Frank Gonzalez
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Gary Lopaschuk
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
| | - Hossein Ardehali
- Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Alberta, Edmonton, Canada. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA
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Scott C, Bonner J, Min D, Boughton P, Stokes R, Cha KM, Walters SN, Maslowski K, Sierro F, Grey ST, Twigg S, McLennan S, Gunton JE. Reduction of ARNT in myeloid cells causes immune suppression and delayed wound healing. Am J Physiol Cell Physiol 2014; 307:C349-57. [PMID: 24990649 DOI: 10.1152/ajpcell.00306.2013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor that binds to partners to mediate responses to environmental signals. To investigate its role in the innate immune system, floxed ARNT mice were bred with lysozyme M-Cre recombinase animals to generate lysozyme M-ARNT (LAR) mice with reduced ARNT expression. Myeloid cells of LAR mice had altered mRNA expression and delayed wound healing. Interestingly, when the animals were rendered diabetic, the difference in wound healing between the LAR mice and their littermate controls was no longer present, suggesting that decreased myeloid cell ARNT function may be an important factor in impaired wound healing in diabetes. Deferoxamine (DFO) improves wound healing by increasing hypoxia-inducible factors, which require ARNT for function. DFO was not effective in wounds of LAR mice, again suggesting that myeloid cells are important for normal wound healing and for the full benefit of DFO. These findings suggest that myeloid ARNT is important for immune function and wound healing. Increasing ARNT and, more specifically, myeloid ARNT may be a therapeutic strategy to improve wound healing.
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Affiliation(s)
- Christopher Scott
- Diabetes and Transcription Factors Group, Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
| | - James Bonner
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Danqing Min
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Philip Boughton
- St. George Clinical School, St. George Hospital, Kogarah, New South Wales, Australia; Department of Biomedical Engineering, University of Sydney, Sydney, New South Wales, Australia
| | - Rebecca Stokes
- Diabetes and Transcription Factors Group, Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Kuan Minn Cha
- Diabetes and Transcription Factors Group, Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Stacey N Walters
- Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Kendle Maslowski
- Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
| | - Frederic Sierro
- Liver Immunology, Centenary Institute, Sydney, New South Wales, Australia
| | - Shane T Grey
- Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Stephen Twigg
- Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Susan McLennan
- Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Jenny E Gunton
- Diabetes and Transcription Factors Group, Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia; and Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, New South Wales, Australia
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Lalwani A, Stokes RA, Lau SM, Gunton JE. Deletion of ARNT (Aryl hydrocarbon receptor nuclear translocator) in β-cells causes islet transplant failure with impaired β-cell function. PLoS One 2014; 9:e98435. [PMID: 24878748 PMCID: PMC4039512 DOI: 10.1371/journal.pone.0098435] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Accepted: 05/03/2014] [Indexed: 01/13/2023] Open
Abstract
Background Replacing β-cells by islet-transplantation can cure type 1 diabetes, but up to 70% of β-cells die within 10 days of transplantation. ARNT (Aryl hydrocarbon Receptor Nuclear Translocator) regulates β-cell function, and potentially survival. Lack of ARNT impairs the ability of β-cells to respond to physiological stress and potentiates the onset of diabetes, but the exact role of ARNT in graft outcome is unknown. Aim To investigate the effect of β-cell deletion of ARNT on graft outcomes. Methods Islets were isolated from donor mice which had β-cell specific ARNT-deletion (β-ARNT) or littermate floxed controls. The islets were transplanted into diabetic SCID recipients in ratios of (a) 3 donors: 1 recipient, (b) 1 donor: 1 recipient or (c) ½ of the islets from 1 donor: 1 recipient. After 28 days, the kidney containing the graft was removed (nephrectomy) to exclude regeneration of the endogenous pancreas. Results In the supra-physiological-mass model (3∶1), both groups achieved reasonable glycaemia, with slightly higher levels in β-ARNT-recipients. In adequate-mass model (1∶1), β-ARNT recipients had poor glucose control versus floxed-control recipients and versus the β-ARNT donors. In the low-β-cell-mass model (½:1) β-ARNT transplants completely failed, whereas controls had good outcomes. Unexpectedly, there was no difference in the graft insulin content or β-cell mass between groups indicating that the defect was not due to early altered β-cell survival. Conclusion Outcomes for islet transplants lacking β-cell ARNT were poor, unless markedly supra-physiological masses of islets were transplanted. In the 1∶1 transplant model, there was no difference in β-cell volume. This is surprising because transplants of islets lacking one of the ARNT-partners HIF-1α have increased apoptosis and decreased islet volume. ARNT also partners HIF-2α and AhR (aryl hydrocarbon receptor) to form active transcriptional complexes, and further work to understand the roles of HIF-2α and AhR in transplant outcomes is needed.
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Affiliation(s)
- Amit Lalwani
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, Australia
- Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, Australia
| | - Rebecca A. Stokes
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, Australia
| | - Sue Mei Lau
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, Australia
- St Vincent’s Clinical School, University of New South Wales, Sydney, Australia
| | - Jenny E. Gunton
- Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, Australia
- Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, Australia
- St Vincent’s Clinical School, University of New South Wales, Sydney, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, Australia
- * E-mail:
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Ramayo-Caldas Y, Ballester M, Fortes MRS, Esteve-Codina A, Castelló A, Noguera JL, Fernández AI, Pérez-Enciso M, Reverter A, Folch JM. From SNP co-association to RNA co-expression: novel insights into gene networks for intramuscular fatty acid composition in porcine. BMC Genomics 2014; 15:232. [PMID: 24666776 PMCID: PMC3987146 DOI: 10.1186/1471-2164-15-232] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 03/21/2014] [Indexed: 12/19/2022] Open
Abstract
Background Fatty acids (FA) play a critical role in energy homeostasis and metabolic diseases; in the context of livestock species, their profile also impacts on meat quality for healthy human consumption. Molecular pathways controlling lipid metabolism are highly interconnected and are not fully understood. Elucidating these molecular processes will aid technological development towards improvement of pork meat quality and increased knowledge of FA metabolism, underpinning metabolic diseases in humans. Results The results from genome-wide association studies (GWAS) across 15 phenotypes were subjected to an Association Weight Matrix (AWM) approach to predict a network of 1,096 genes related to intramuscular FA composition in pigs. To identify the key regulators of FA metabolism, we focused on the minimal set of transcription factors (TF) that the explored the majority of the network topology. Pathway and network analyses pointed towards a trio of TF as key regulators of FA metabolism: NCOA2, FHL2 and EP300. Promoter sequence analyses confirmed that these TF have binding sites for some well-know regulators of lipid and carbohydrate metabolism. For the first time in a non-model species, some of the co-associations observed at the genetic level were validated through co-expression at the transcriptomic level based on real-time PCR of 40 genes in adipose tissue, and a further 55 genes in liver. In particular, liver expression of NCOA2 and EP300 differed between pig breeds (Iberian and Landrace) extreme in terms of fat deposition. Highly clustered co-expression networks in both liver and adipose tissues were observed. EP300 and NCOA2 showed centrality parameters above average in the both networks. Over all genes, co-expression analyses confirmed 28.9% of the AWM predicted gene-gene interactions in liver and 33.0% in adipose tissue. The magnitude of this validation varied across genes, with up to 60.8% of the connections of NCOA2 in adipose tissue being validated via co-expression. Conclusions Our results recapitulate the known transcriptional regulation of FA metabolism, predict gene interactions that can be experimentally validated, and suggest that genetic variants mapped to EP300, FHL2, and NCOA2 modulate lipid metabolism and control energy homeostasis in pigs.
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Affiliation(s)
- Yuliaxis Ramayo-Caldas
- Centre de Recerca en Agrigenòmica (CRAG), Consorci CSIC-IRTA-UAB-UB, Campus UAB, Bellaterra 08193, Spain.
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Micro-architectural changes in cancellous bone differ in female and male C57BL/6 mice with high-fat diet-induced low bone mineral density. Br J Nutr 2014; 111:1811-21. [DOI: 10.1017/s0007114514000051] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The relationship between fat and bone mass at distinct trabecular and cortical skeletal compartments in a high-fat diet (HFD) model was studied. For this, C57BL/6 mice were assigned to four groups of eight animals each. Two groups, each of males and females, received a standard chow diet while the remaining other two groups received the HFD for a period of 10 weeks. Male mice on the HFD were heavier and gained more weight (15·8 %; P< 0·05) v. those on the control diet or when compared with the female rats fed the HFD. We observed an increased lipid profile in both males and females, with significantly higher lipid levels (about 20–25 %; P< 0·01) in males. However, glucose intolerance was more pronounced in females than males on the HFD (about 30 %; P< 0·05). The micro-architectural assessment of bones showed that compared with female mice on the HFD, male mice on the HFD showed more deterioration at the trabecular region. This was corroborated by plasma osteocalcin and carboxy-terminal collagen crosslinks (CTx) levels confirming greater loss in males (about 20 %; P< 0·01). In both sexes cortical bone parameters and strength remained unchanged after 10 weeks of HFD treatment. The direct effect of the HFD on bone at the messenger RNA level in progenitor cells isolated from femoral bone marrow was a significantly increased expression of adipogenic marker genes v. osteogenic genes. Overall, the present data indicate that obesity induced by a HFD aggravates bone loss in the cancellous bone compartment, with a greater loss in males than females, although 10 weeks of HFD treatment did not alter cortical bone mass and strength in both males and females.
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Wei K, Piecewicz SM, McGinnis LM, Taniguchi CM, Wiegand SJ, Anderson K, Chan CWM, Mulligan KX, Kuo D, Yuan J, Vallon M, Morton L, Lefai E, Simon MC, Maher JJ, Mithieux G, Rajas F, Annes J, McGuinness OP, Thurston G, Giaccia AJ, Kuo CJ. A liver Hif-2α-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nat Med 2013; 19:1331-1337. [PMID: 24037094 PMCID: PMC3795838 DOI: 10.1038/nm.3295] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 07/09/2013] [Indexed: 12/24/2022]
Abstract
Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein. Further, liver Irs2 was both necessary and sufficient to mediate Hif-2α and Vegf inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between Hif-2α-mediated hypoxic signaling and hepatic insulin action through Irs2 induction, which can be co-opted by Vegf inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for Hif-1α, which promotes glycolysis, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.
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Affiliation(s)
- Kevin Wei
- Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Stephanie M. Piecewicz
- Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Lisa M. McGinnis
- Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Cullen M. Taniguchi
- Division of Radiation Oncology Stanford University School of Medicine, Stanford, California 94305, USA
| | - Stanley J. Wiegand
- Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York, 10591, USA
| | - Keith Anderson
- Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York, 10591, USA
| | - Carol W-M. Chan
- Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Kimberly X. Mulligan
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville TN 37232, USA
| | - David Kuo
- Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Jenny Yuan
- Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Mario Vallon
- Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Lori Morton
- Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York, 10591, USA
| | - Etienne Lefai
- INSERM U 1060, INRA 1235, Universite de Lyon, Faculté de Médecine Lyon Sud - BP12, 69921 OULLINS Cedex, France
| | - M. Celeste Simon
- Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA
| | - Jacquelyn J. Maher
- UCSF Liver Center, San Francisco General Hospital, 1001 Potrero Ave. Building 40, Room 4102, San Francisco, CA 94110
| | - Gilles Mithieux
- Inserm U855/Université Lyon, Faculté Lyon Est Laennec, 7 rue Guillaume Paradin, 69372 Lyon cedex 08, France
| | - Fabienne Rajas
- Inserm U855/Université Lyon, Faculté Lyon Est Laennec, 7 rue Guillaume Paradin, 69372 Lyon cedex 08, France
| | - Justin Annes
- Division of Endocrinology and Metabolism, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Owen P. McGuinness
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville TN 37232, USA
| | - Gavin Thurston
- Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York, 10591, USA
| | - Amato J. Giaccia
- Division of Radiation Oncology Stanford University School of Medicine, Stanford, California 94305, USA
| | - Calvin J. Kuo
- Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
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La Merrill M, Emond C, Kim MJ, Antignac JP, Le Bizec B, Clément K, Birnbaum LS, Barouki R. Toxicological function of adipose tissue: focus on persistent organic pollutants. ENVIRONMENTAL HEALTH PERSPECTIVES 2013; 121:162-9. [PMID: 23221922 PMCID: PMC3569688 DOI: 10.1289/ehp.1205485] [Citation(s) in RCA: 254] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 12/04/2012] [Indexed: 05/17/2023]
Abstract
BACKGROUND Adipose tissue (AT) is involved in several physiological functions, including metabolic regulation, energy storage, and endocrine functions. OBJECTIVES In this review we examined the evidence that an additional function of AT is to modulate persistent organic pollutant (POP) toxicity through several mechanisms. METHODS We reviewed the literature on the interaction of AT with POPs to provide a comprehensive model for this additional function of AT. DISCUSSION As a storage compartment for lipophilic POPs, AT plays a critical role in the toxicokinetics of a variety of drugs and pollutants, in particular, POPs. By sequestering POPs, AT can protect other organs and tissues from POPs overload. However, this protective function could prove to be a threat in the long run. The accumulation of lipophilic POPs will increase total body burden. These accumulated POPs are slowly released into the bloodstream, and more so during weight loss. Thus, AT constitutes a continual source of internal exposure to POPs. In addition to its buffering function, AT is also a target of POPs and may mediate part of their metabolic effects. This is particularly relevant because many POPs induce obesogenic effects that may lead to quantitative and qualitative alterations of AT. Some POPs also induce a proinflammatory state in AT, which may lead to detrimental metabolic effects. CONCLUSION AT appears to play diverse functions both as a modulator and as a target of POPs toxicity.
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Affiliation(s)
- Michele La Merrill
- Department of Preventive Medicine, Mount Sinai School of Medicine, New York, New York, USA
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Yogosawa S, Mizutani S, Ogawa Y, Izumi T. Activin receptor-like kinase 7 suppresses lipolysis to accumulate fat in obesity through downregulation of peroxisome proliferator-activated receptor γ and C/EBPα. Diabetes 2013; 62:115-23. [PMID: 22933117 PMCID: PMC3526038 DOI: 10.2337/db12-0295] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
We previously identified a quantitative trait locus for adiposity, non-insulin-dependent diabetes 5 (Nidd5), on mouse chromosome 2. In the current study, we identified the actual genetic alteration at Nidd5 as a nonsense mutation of the Acvr1c gene encoding activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-β receptors, which results in a COOH-terminal deletion of the kinase domain. We further showed that the ALK7 dysfunction causes increased lipolysis in adipocytes and leads to decreased fat accumulation. Conversely, ALK7 activation inhibits lipolysis by suppressing the expression of adipose lipases. ALK7 and activated Smads repress those lipases by downregulating peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBP) α. Although PPARγ and C/EBPα act as adipogenic transcription factors during adipocyte differentiation, they are lipolytic in sum in differentiated adipocytes and are downregulated by ALK7 in obesity to accumulate fat. Under the obese state, ALK7 deficiency improves glucose tolerance and insulin sensitivity by preferentially increasing fat combustion in mice. These findings have uncovered a net lipolytic function of PPARγ and C/EBPα in differentiated adipocytes and point to the ALK7-signaling pathway that is activated in obesity as a potential target of medical intervention.
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Affiliation(s)
- Satomi Yogosawa
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Shin Mizutani
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Yoshihiro Ogawa
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tetsuro Izumi
- Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
- Corresponding author: Tetsuro Izumi,
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Xiao H, Gu Z, Wang G, Zhao T. The possible mechanisms underlying the impairment of HIF-1α pathway signaling in hyperglycemia and the beneficial effects of certain therapies. Int J Med Sci 2013; 10:1412-21. [PMID: 23983604 PMCID: PMC3752727 DOI: 10.7150/ijms.5630] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 07/23/2013] [Indexed: 01/07/2023] Open
Abstract
Hypoxia-inducible factor 1 alpha (HIF-1α), an essential transcription factor which mediates the adaptation of cells to low oxygen tensions, is regulated precisely by hypoxia and hyperglycemia, which are major determinants of the chronic complications associated with diabetes. The process of HIF-1α stabilization by hypoxia is clear; however, the mechanisms underlying the potential deleterious effect of hyperglycemia on HIF-1α are still controversial, despite reports of a variety of studies demonstrating the existence of this phenomenon. In fact, HIF-1α and glucose can sometimes influence each other: HIF-1α induces the expression of glycolytic enzymes and glucose metabolism affects HIF-1α accumulation in some cells. Although hyperglycemia upregulates HIF-1α signaling in some specific cell types, we emphasize the inhibition of HIF-1α by high glucose in this review. With regard to the mechanisms of HIF-1α impairment, the role of methylglyoxal in impairment of HIF-1α stabilization and transactivation ability and the negative effect of reactive oxygen species (ROS) on HIF-1α are discussed. Other explanations for the inhibition of HIF-1α by high glucose exist: the increased sensitivity of HIF-1α to Von Hippel-Lindau (VHL) machinery, the role of osmolarity and proteasome activity, and the participation of several molecules. This review aims to summarize several important developments regarding these mechanisms and to discuss potentially effective therapeutic techniques (antioxidants eicosapentaenoic acid (EPA) and metallothioneins (MTs), pharmaceuticals cobalt chloride (CoCl2), dimethyloxalylglycine (DMOG), desferrioxamine (DFO) and gene transfer of constitutively active forms of HIF-1α) and their mechanisms of action for intervention in the chronic complications in diabetes.
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Affiliation(s)
- Haijuan Xiao
- Department of Endocrinology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
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Jiang C, Kim JH, Li F, Qu A, Gavrilova O, Shah YM, Gonzalez FJ. Hypoxia-inducible factor 1α regulates a SOCS3-STAT3-adiponectin signal transduction pathway in adipocytes. J Biol Chem 2012; 288:3844-57. [PMID: 23255598 DOI: 10.1074/jbc.m112.426338] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Obesity has been identified as a major risk factor for type 2 diabetes, characterized by insulin resistance in insulin target tissues. Hypoxia-inducible factor 1α (HIF1α) regulates pathways in energy metabolism that become dysregulated in obesity. Earlier studies revealed that HIF1α in adipose tissue is markedly elevated in high-fat diet-fed mice that are obese and insulin-resistant. Genetic ablation of HIF1α in adipose tissue decreased insulin resistance and obesity, accompanied by increased serum adiponectin levels. However, the exact mechanism whereby HIF1α regulates adiponectin remains unclear. Here, acriflavine (ACF), an inhibitor of HIF1α, induced the expression of adiponectin and reduced the expression of SOCS3 in cultured 3T3-L1 adipocytes. Mechanistic studies revealed that HIF1α suppressed the expression of adiponectin through a SOCS3-STAT3 pathway. Socs3 was identified as a novel HIF1α target gene based on chromatin immunoprecipitation and luciferase assays. STAT3 directly regulated adiponectin in vitro in cultured 3T3-L1 adipocytes. ACF was found to prevent diet-induced obesity and insulin resistance. In vivo, ACF also regulated the SOCS3-STAT3-adiponectin pathway, and inhibition of HIF1α in adipose tissue was essential for ACF to improve the SOCS3-STAT3-adiponectin pathway to counteract insulin resistance. This study provides evidence for a novel target gene and signal transduction pathway in adipocytes and indicates that inhibitors of HIF1α have potential utility for the treatment of obesity and type 2 diabetes.
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Affiliation(s)
- Changtao Jiang
- Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA
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