Adiponectin Reduces Hepatic Stellate Cell Migration by Promoting Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Secretion

Ramezani-Moghadam, Mehdi; Wang, Jianhua; Ho, Vikki; Iseli, Tristan J.; Alzahrani, Badr; Xu, Aimin; Poorten, David van der; Qiao, Liang; George, Jacob; Hebbard, Lionel

doi:10.1074/jbc.m114.598011

Cited by 52 publications

(41 citation statements)

References 38 publications

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“…Reductions in adiponectin were contrary to improved glucose tolerance, but consistent with increased fibrosis because adiponectin inhibits myofibroblast proliferation and mobility (Ramezani-Moghadam et al, 2015). TIMP-1 which was induced by TCDD cooperates with adiponectin to reduce fibrogenic activity (Ramezani-Moghadam et al, 2015), although other studies suggest profibrogenic interactions (Yoshiji et al, 2000). IFN-c blocks fibrogenesis by inhibiting TGFb/Smad signaling (Weng et al, 2007).…”

Section: Discussionmentioning

confidence: 91%

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Nault¹,

Fader²,

Ammendolia³

et al. 2016

Toxicol. Sci.

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We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 mg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1b, -2, -4, -6, and -10, as well as TNF-a and IFN-c, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNASeq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.

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Section: Discussionmentioning

confidence: 91%

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Nault¹,

Fader²,

Ammendolia³

et al. 2016

Toxicol. Sci.

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“…Leptin reduces expression of sterol regulatory element-binding protein-1c (SREBP-1c) and activates HSCs through involvement of β-catenin pathway [190]. Adiponectin attenuates liver fibrosis by inducing nitric oxide (NO) production via adipoR2-AMP-activated protein kinase (AMPK)-JNK/ErK1/2-NF-κB pathway and TIMP-1, and inhibits proliferation and migration of activated HSCs [191, 192]. Adiponectin induces expression of aquaglyceroporin (known to be down-regulated in association with obesity) and inactivates HSCs [193].…”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

976

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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“…For example, adiponectin prevents proliferation and migration of HSCs [18], as well as decreases ECM deposition via alteration of molecular ratio of MMP-1 to TIMP-1 (by increasing TIMP-1 expression, and/or decreasing MMP-1 expression) [19]. Adiponectin also sensitizes activated HSCs to caspase-mediated apoptosis [20].…”

Section: Adiponectinmentioning

confidence: 99%

“…Inhibition of TIMP-1 is a potential mechanism underlying anti-fibrotic effects of adiponectin [99]; however, the data from different studies are not all supportive of this hypothesis. In one study, treatment of HSCs with adiponectin promoted expression of TIMP-1 and binding of TIMP-1 with C63/β1-integrin complex reduced phosphorylation of FAK, which suppressed the migration of HSCs [18]. In addition, treatment with adiponectin increases mRNA level of TIMP-1 in dermal fibroblasts [100] and macrophages via Syk-dependent manner [78].…”

Section: Molecular Mechanisms Underlying Regulation Of Fibrosis and Imentioning

confidence: 99%

Adiponectin as an Anti-fibrotic and Anti-inflammatory Adipokine in the Liver

2015

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Hepatic fibrosis is a dynamic process resulting from excessive deposition of extracellular matrix in the liver; uncontrolled progression of fibrosis can eventually lead to liver cirrhosis and/or hepatocellular carcinoma. The fibrogenic process is complex and modulated by a number of both hepatic and extra-hepatic biological factors. Growing evidence indicates that adipokines, a group of cytokines produced by adipose tissue, impart dynamic functions in liver and are involved in modulation of hepatic fibrosis. In particular, two key adipokines, adiponectin and leptin, directly regulate many biological responses closely associated with development and progression of hepatic fibrosis. Leptin acts as a pro-fibrogenic cytokine, while adiponectin possesses anti-fibrogenic and anti-inflammatory properties. Adiponectin, acting via its cognate receptors, adiponectin receptors 1 and 2, potently suppresses fibrosis and inflammation in liver via multiple mechanisms. This review summarizes recent findings concerning the role of adiponectin in fibrogenic process in liver and addresses the underlying molecular mechanisms in modulation of fibrosis.

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Adiponectin Reduces Hepatic Stellate Cell Migration by Promoting Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Secretion

Cited by 52 publications

References 38 publications

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Hepatic stellate cells as key target in liver fibrosis

Adiponectin as an Anti-fibrotic and Anti-inflammatory Adipokine in the Liver

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