Adiponectin, bile acids, and burnt-out nonalcoholic steatohepatitis: New light on an old paradox

Claudel, Thierry; Trauner, Michael

doi:10.1002/hep.26340

Cited by 10 publications

(6 citation statements)

References 73 publications

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“…Paradoxically, hepatic Cyp7a1 mRNA levels were slightly increased in gAcrp-treated mice compared to controls, implying that gAcrp may also directly regulate hepatic Cyp7A1 gene expression ( Fig. 7E ) 28 29 .…”

Section: Resultsmentioning

confidence: 98%

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Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice

Wang

Kim

Jogasuria

et al. 2016

Sci Rep

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Lipin-1 is a phosphatidate phosphohydrolase (PAP) required for the generation of diacylglycerol during glycerolipid synthesis, and exhibits dual functions in the regulation of lipid metabolism. Lipin-1 has been implicated in the pathogenesis of alcoholic liver disease (ALD). In the present study, we assessed lipin-1 function in myeloid cells in ALD using a myeloid cell-specific lipin-1 knockout (mLipin-1KO) mouse model. Utilizing the Gao-binge ethanol feeding protocol, matched mLipin-1KO mice and littermate loxP control (WT) mice were pair-fed with either an ethanol-containing diet or an ethanol-free diet (control). Surprisingly, deletion of lipin-1 in myeloid cells dramatically attenuated liver inflammatory responses and ameliorated liver injury that would normally occur following the ethanol feeding protocol, but slightly exacerbated the ethanol-induced steatosis in mice. Mechanistically, myeloid cell-specific lipin-1 deficiency concomitantly increased the fat-derived adiponectin and ileum-derived fibroblast growth factor (FGF) 15. In concordance with concerted elevation of circulating adiponectin and FGF15, myeloid cell-specific lipin-1 deficiency diminished hepatic nuclear factor kappa B (NF-κB) activity, limited liver inflammatory responses, normalized serum levels of bile acids, and protected mice from liver damage after ethanol challenge. Our novel data demonstrate that myeloid cell-specific deletion of lipin-1 ameliorated inflammation and alcoholic hepatitis in mice via activation of endocrine adiponectin-FGF15 signaling.

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Section: Resultsmentioning

confidence: 98%

“…Both adiponectin and FGF15/19 are capable of regulating bile acid hemostasis 25 26 28 29 . Hence, we examined whether hepatic myeloid cell-specific lipin-1 deficiency affects bile acid homeostasis.…”

Section: Resultsmentioning

confidence: 99%

Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice

Wang

Kim

Jogasuria

et al. 2016

Sci Rep

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“…It is now clear that bile acid function as hormones or nutrient signaling molecules that help to regulate glucose, lipid, lipoprotein, energy metabolism and inflammatory responses (5, 6). The role of bile acid-mediated signaling pathways in nonalcoholic fatty liver diseases has been discussed in several excellent reviews (8–12). In this brief review, we will focus on how the insulin signaling pathway and FXR-α cross-talk to regulate hepatic nutrient metabolism.…”

Section: Introductionmentioning

confidence: 99%

Bile acids are nutrient signaling hormones

2014

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Bile salts play crucial roles in allowing the gastrointestinal system to digest, transport and metabolize nutrients. They function as nutrient signaling hormones by activating specific nuclear receptors (FXR, PXR, Vitamin D) and G-protein coupled receptors [TGR5, sphingosine-1 phosphate receptor 2 (S1PR2), muscarinic receptors]. Bile acids and insulin appear to collaborate in regulating the metabolism of nutrients in the liver. They both activate the AKT and ERK1/2 signaling pathways. Bile acid induction of the FXR-α target gene, small heterodimer partner (SHP), is highly dependent on the activation PKCζ, a branch of the insulin signaling pathway. SHP is an important regulator of glucose and lipid metabolism in the liver. One might hypothesize that chronic low grade inflammation which is associated with insulin resistance, may inhibit bile acid signaling and disrupt lipid metabolism. The disruption of these signaling pathways may increase the risk of fatty liver and non-alcoholic fatty liver disease (NAFLD). Finally, conjugated bile acids appear to promote cholangiocarcinoma growth via the activation of S1PR2.

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“…Accumulation of HBsAg in the ER induces stress, which activates UPRs for protein degradation, and increases the lipid content of hepatocytes through unidentified mechanisms [8] , [26] . Surprisingly, the pronounced hepatic lipid accumulation disappeared over time in some HBV carriers who developed cryptogenic HCC, a phenomenon of the so-called “burn-out steatosis” [27] , [28] , [29] , [30] . The molecular mechanism explaining the metabolic paradox in shifting from lipogenesis to lipolysis during HBV-related pathogenesis remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

The Role of Promyelocytic Leukemia Protein in Steatosis-Associated Hepatic Tumors Related to Chronic Hepatitis B virus Infection

Chung

2018

Translational Oncology

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The persistence of hepatitis B surface antigen (HBsAg) is a risk factor for the development of steatosis-associated tumors in chronic hepatitis B virus (HBV) infection, yet little is known about the metabolic link with this factor. We correlated HBV-related pathogenesis in genetically engineered mice and human carriers with metabolic proteomics and lipogenic gene expression profiles. The immunohistochemistry showed that the promyelocytic leukemia protein (PML, a tumor suppressor involved in genome maintenance and fatty acid oxidation), being inversely influenced by the dynamic HBsAg levels from acute phase to seroclearance, appeared as a lipo-metabolic switch linking HBsAg-induced steatosis (lipogenesis) to HBsAg-lost fat-burning hepatocarcinogenesis (lipolysis). Knockdown of PML in HBsAg-transgenic mice predisposed to obesity and drove early steatosis-specific liver tumorigenesis. Proteome analysis revealed that the signaling pathways corresponding to energy metabolism and its regulators were frequently altered by suppression or depletion of PML in the HBsAg-transgenic mice, mainly including oxidative phosphorylation and fatty acid metabolism. Expression profiling further identified upregulation of stearoyl-CoA desaturase 1 (Scd1) and epigenetic methylation of NDUFA13 in the mitochondrial respiratory chain and the cell cycle inhibitor CDKN1c in concordance to the increased severity of lipodystrophy and neoplasia in the livers of HBsAg-transgenic mice with PML insufficiency. The defect in lipolysis in PML-deficient HBsAg-transgenic mice made the HBsAg-induced adipose-like liver tumors vulnerable to synthetic lethality from toxic saturated fat accumulation with a Scd1 inhibitor. Our findings provide mechanistic insights into the evolution of steatosis-associated hepatic tumors driven by reciprocal interactions of HBsAg and PML, and a potential utility of lipid metabolic reprogramming as a treatment target.

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Adiponectin, bile acids, and burnt-out nonalcoholic steatohepatitis: New light on an old paradox

Cited by 10 publications

References 73 publications

Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice

Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice

Bile acids are nutrient signaling hormones

The Role of Promyelocytic Leukemia Protein in Steatosis-Associated Hepatic Tumors Related to Chronic Hepatitis B virus Infection

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