The role of AdipoR1 and AdipoR2 in liver fibrosis

Alzahrani, Badr; Iseli, Tristan J.; Ramezani-Moghadam, Mehdi; Ho, Vikki; Wankell, Miriam; Sun, Eun Jin; Qiao, Liang; George, Jacob; Hebbard, Lionel

doi:10.1016/j.bbadis.2017.12.012

Cited by 28 publications

(18 citation statements)

References 24 publications

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“…Hepatic stellate cells (HSC) and Kupffer cells constitutively express the same amount of AdipoR1 and AdipoR2 [ 15 , 16 ]. HSC are activated following a trauma and lead to the secretion of collagen and to the formation of scar tissue, leading to chronic fibrosis or cirrhosis.…”

Section: Adiponectin In Healthy Livermentioning

confidence: 99%

Adiponectin Signaling Pathways in Liver Diseases

et al. 2018

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In the liver, adiponectin regulates both glucose and lipid metabolism and exerts an insulin-sensitizing effect. The binding of adiponectin with its specific receptors induces the activation of a proper signaling cascade that becomes altered in liver pathologies. This review describes the different signaling pathways in healthy and diseased hepatocytes, also highlighting the beneficial role of adiponectin in autophagy activation and hepatic regeneration.

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Section: Adiponectin In Healthy Livermentioning

confidence: 99%

Adiponectin Signaling Pathways in Liver Diseases

et al. 2018

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“…A host of factors contribute to the trans-differentiation of HSCs to mature myofibroblasts, including transforming growth factor (TGF-β), platelet derived growth factor (PDGF-BB), high glucose, and reactive oxygen species (ROS) (Liu and Desai, 2015;Alzahrani et al, 2018;Hou and Syn, 2018;Jia et al, 2018). ROS production, similar to fibrogenesis, is also considered a host defense mechanism (Sies, 2015).…”

Section: Introductionmentioning

confidence: 99%

CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels

Kong

et al. 2020

Front. Cell Dev. Biol.

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The lipid-storage hepatic stellate cells (HSC) play as pivotal role in liver fibrosis being able to trans-differentiate into myofibroblasts in response to various pro-fibrogenic stimuli. In the present study we investigated the role of CDKN2a/p16, a negative regulator of cell cycling, in HSC activation and the underlying mechanism. Levels of p16 were significantly down-regulated in activated HSCs isolated from mice induced to develop liver fibrosis compared to quiescent HSCs isolated from the control mice ex vivo. There was a similar decrease in p16 expression in cultured HSCs undergoing spontaneous activation or exposed to TGF-β treatment in vitro. More important, p16 down-regulation was observed to correlate with cirrhosis in humans. In a classic model of carbon tetrachloride (CCl 4 ) induced liver fibrosis, fibrogenesis was far more extensive in mice with p16 deficiency (KO) than the wild type (WT) littermates. Depletion of p16 in cultured HSCs promoted the synthesis of extracellular matrix (ECM) proteins. Mechanistically, p16 deficiency accelerated reactive oxygen species (ROS) generation in HSCs likely through the p38 MAPK signaling. P38 inhibition or ROS cleansing attenuated ECM production in p16 deficient HSCs. Taken together, our data unveil a previously unappreciated role for p16 in the regulation of HSC activation. Screening for smallmolecule compounds that can boost p16 activity may yield novel therapeutic strategies against liver fibrosis.

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“…We and others have recently demonstrated that adiponectin, a 30 kDa adipocytokine primarily secreted by white adipose tissue (WAT), has anti-fibrotic properties both in vivo and in vitro [6–10]. Adiponectin signaling occurs via its two cognate receptors: adiponectin receptor 1 and 2 [11,12]. However, the molecular mechanism responsible for anti-fibrotic effects induced by adiponectin remained unexplored.…”

Section: Introductionmentioning

confidence: 99%

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Kumar¹,

Raeman²,

Chopyk³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Adiponectin inhibits hepatic stellate cell (HSC) activation and subsequent development of liver fibrosis via multiple mechanisms. Phosphatase and tensin homolog deletion 10 (PTEN) plays a crucial role in suppression of HSC activation, but its regulation by adiponectin is not fully understood. Here, we investigated the effect of adiponectin on PTEN in LX-2 cells, a human cell line and examined the underlying molecular mechanisms involved in adiponectin-mediated upregulation of PTEN activity during fibrosis. PTEN expression was found to be significantly reduced in the livers of mice treated with CCl4, whereas its expression was rescued by adiponectin treatment. The DNA methylation proteins DNMT1, DNMT3A, and DNMT3B are all highly expressed in activated primary HSCs compared to quiescent HSCs, and thus represent additional regulatory targets during liver fibrogenesis. Expression of DNMT proteins was significantly induced in the presence of fibrotic stimuli; however, only DNMT3B expression was reduced in the presence of adiponectin. Adiponectin-induced suppression of DNMT3B was found to be mediated by enhanced miR-29b expression. Furthermore, PTEN expression was significantly increased by overexpression of miR-29b, whereas its expression was markedly reduced by a miR-29b inhibitor in LX-2 cells. These findings suggest that adiponectin-induced upregulation of miR-29b can suppress DNMT3B transcription in LX-2 cells, thus resulting in reduced methylation of PTEN CpG islands and ultimately suppressing the PI3K/AKT pathway. Together, these data suggest a possible new explanation for the inhibitory effect of adiponectin on HSC activation and liver fibrogenesis.

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The role of AdipoR1 and AdipoR2 in liver fibrosis

Cited by 28 publications

References 24 publications

Adiponectin Signaling Pathways in Liver Diseases

Adiponectin Signaling Pathways in Liver Diseases

CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

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