Lipid accumulation impairs adiponectin-mediated induction of activin A by increasing TGFbeta in primary human hepatocytes

Wanninger, Josef; Neumeier, Markus; Hellerbrand, Claus; Schacherer, Doris; Bauer, Sabrina; Weiss, Thomas S.; Huber, Hanna; Schäffler, Andréas; Aslanidis, Charalampos; Schölmerich, Jürgen; Buechler, Christa

doi:10.1016/j.bbalip.2010.11.001

Cited by 40 publications

(31 citation statements)

References 43 publications

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“…Production of collagen (and other components of the ECM) is potently stimulated by tissue growth factor-beta (TGFβ) [71]. (Lipid accumulation in hepatocytes has also been shown to induce TGFβ signalling and impair adiponectin activity, supporting a key role for FFAs in the development of hepatic fibrosis) [72]. Other important stimuli of ECM production include lipid peroxidation products [73] and connective tissue growth factor (CTGF) [74].…”

Section: Progressive Nash: From Inflammation To Fibrosismentioning

confidence: 99%

Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation

Peverill

Powell

Skoien

2014

IJMS

310

243

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Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future.

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Section: Progressive Nash: From Inflammation To Fibrosismentioning

confidence: 99%

Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation

Peverill

Powell

Skoien

2014

IJMS

310

243

View full text Add to dashboard Cite

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“…1C, D). Cultivation of PHH in the presence of oleate or palmitate increased cellular triglycerides [28] but again SR-BI protein was not altered (Fig. 1E).…”

Section: Regulation Of Sr-bi By Factors With a Role In Nafldmentioning

confidence: 76%

Hepatic scavenger receptor BI is associated with type 2 diabetes but unrelated to human and murine non-alcoholic fatty liver disease

Rein-Fischboeck

Krautbauer

Eisinger

et al. 2015

Biochemical and Biophysical Research Communications

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“…Our group has shown that HMW-APN upregulates the pro-fibrotic and anti-steatotic protein, activin A, and suppresses its natural inhibitor, follistatin [7,27]. HMW-APN also increases MMP-9 and TIMP-1, which participate in extracellular matrix degradation [8,28].…”

Section: Resultsmentioning

confidence: 99%

“…This adipokine exerts insulin-sensitizing, anti-steatotic and anti-fibrotic activities [2]. Various hepatic genes involved in mitochondrial function, fibrosis, lipid and glucose metabolism are regulated by this adipokine [3,4,5,6,7,8,9]. APN also protects hepatocytes from apoptosis by antagonizing free fatty acid-induced CD95 expression [10].…”

Section: Introductionmentioning

confidence: 99%

“…Here, recombinant human LMW-APN produced in insect cells and recombinant human HMW-APN expressed in a mouse cell line [16] have been used to study the effects of these APN isoforms on the expression of genes already described to be regulated by HMW-APN in primary human hepatocytes (PHH) [5,7,8]. Fibroblast growth factor 21 (FGF21) turned out to exert its metabolic function by the induction of adiponectin [24], and therefore, the regulation of hepatocyte FGF21 by APN isoforms has been determined.…”

Section: Introductionmentioning

confidence: 99%

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Adiponectin Isoforms Differentially Affect Gene Expression and the Lipidome of Primary Human Hepatocytes

et al. 2014

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Adiponectin (APN) exerts multiple beneficial effects in obesity and protects from liver injury. Different APN isoforms circulate in serum, and here, the effect of low molecular weight (LMW) and higher molecular weight (HMW) APN on primary human hepatocytes (PHH) has been analyzed. APN is not detected in hepatocyte lysates; levels are strongly increased by HMW-APN, but not by LMW-APN, suggesting the distinct uptake/degradation of APN isoforms by PHH. Several genes with a role in fibrosis, glucose and lipid metabolism known to be regulated by HMW-APN are not affected by the LMW-isoform. Follistatin is reduced by HMW-APN and induced by LMW-APN in supernatants of PHH. Fibroblast growth factor 21 is repressed by both isoforms. Cellular triglycerides and cholesterol levels are not reduced by APN. Total phospholipids, including plasmalogens and sphingomyelins, are not changed upon APN incubation, while distinct species are either induced or repressed. Unexpectedly, total ceramide is increased by LMW-APN. Current data show that APN isoforms differentially affect hepatocyte gene expression, but do not grossly alter the hepatocyte lipidome.

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Lipid accumulation impairs adiponectin-mediated induction of activin A by increasing TGFbeta in primary human hepatocytes

Cited by 40 publications

References 43 publications

Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation

Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation

Hepatic scavenger receptor BI is associated with type 2 diabetes but unrelated to human and murine non-alcoholic fatty liver disease

Adiponectin Isoforms Differentially Affect Gene Expression and the Lipidome of Primary Human Hepatocytes

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