The interplay between hepatic stellate cells and hepatocytes in an in vitro model of NASH

Barbero-Becerra, Varenka J.; Giraudi, Pablo J.; Chávez-Tapia, Norberto C.; Uribe, Misael; Tiribelli, Claudio; Rosso, Natalia

doi:10.1016/j.tiv.2015.07.010

Cited by 55 publications

(44 citation statements)

References 30 publications

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“…Normally, liver damage as seen in steatosis and NASH induces the local production of Hh ligands that stimulate the proliferation and activation of cells involved in liver repair, including HSCs [9, 28]. Sustained hepatic damage induces the expression by HSCs of genes involved in extracellular matrix (ECM) remodeling, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [29]. Pro-inflammatory cytokines also play a major role in liver regeneration and the pathogenesis of NAFLD, in particular the IL1β inflammasome [30], as well as PPARs, which are master regulators of energy metabolism and overall liver function [31].…”

Section: Resultsmentioning

confidence: 99%

“…Contrary to classical NAFLD molecular pathogenesis, the Gli2 +/− mice showed reduced expression of pro-fibrogenic markers when exposed to HF diet. Based on our results, this could be mechanistically explained by a combination of reduced collagen deposition mediated by PPARγ, and increased ECM degradation by MMPs due to decreased expression of TIMPs [29]. Counter-intuitively, MMP-2 is considered a profibrogenic MMP, as it regulates the degradation of basal lamina allowing replacement by fibrillar collagens during fibrogenesis [47].…”

Section: Discussionmentioning

confidence: 99%

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Human germline hedgehog pathway mutations predispose to fatty liver

Guillen-Sacoto

Martinez

Abe

et al. 2017

Journal of Hepatology

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Background & Aims Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations affecting this pathway. Methods Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2+/−) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. Results Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2+/− mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2+/− mice exposed to high-fat diet. Conclusions Our results indicate that germline mutations disrupting Hh signaling promote liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human germline hedgehog pathway mutations predispose to fatty liver

Guillen-Sacoto

Martinez

Abe

et al. 2017

Journal of Hepatology

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“…Several recent studies reported cross-talk between hepatocytes and HSCs as a means of mediating the progression of hepatic fibrosis (52,53). Qian et al (52) demonstrated that hepatocyte nuclear factor 1␣ (HNF1-␣) suppression in hepatocytes enhanced the activation of HSCs, suggesting the presence of an HNF1-␣-modulated feedback circuit between hepatocytes and HSCs.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 (SIRT3) Regulates α-Smooth Muscle Actin (α-SMA) Production through the Succinate Dehydrogenase-G Protein-coupled Receptor 91 (GPR91) Pathway in Hepatic Stellate Cells

Choi

Lee

et al. 2016

Journal of Biological Chemistry

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Sirtuin 3 (SIRT3) is an NAD؉ -dependent protein deacetylase.Recent studies have shown that SIRT3 expression is decreased in nonalcoholic fatty liver disease (NAFLD). Moreover, SIRT3 is a key regulator of succinate dehydrogenase (SDH), which catalyzes the oxidation of succinate to fumarate. Increased succinate concentrations and the specific G protein-coupled receptor 91 (GPR91) are involved in the activation of hepatic stellate cells (HSCs). In this study, we aimed to establish whether SIRT3 regulated the SDH activity, succinate, and GPR91 expression in HSCs and an animal model of NAFLD. Our goal was also to determine whether succinate released from hepatocytes regulated HSC activation. Inhibiting SIRT3 using SIRT3 siRNA exacerbated HSC activation via the SDH-succinate-GPR91 pathway, and SIRT3 overexpression or honokiol treatment attenuated HSC activation in vitro. In isolated liver and HSCs from methionine-and choline-deficient (MCD) diet-induced NAFLD, the expression of SIRT3 and SDH activity was decreased, and the succinate concentrations and GPR91 expression were increased. Moreover, we found that GPR91 knockdown or resveratrol treatment improved the steatosis in MCD diet-fed mice. This investigation revealed a novel mechanism of the SIRT3-SDH-GPR91 cascade in MCD diet-induced HSC activation in NAFLD. These findings highlight the biological significance of novel strategies aimed at targeting SIRT3 and GPR91 in HSCs with the goal of improving NAFLD treatment.Nonalcoholic fatty liver disease (NAFLD) 2 is the most common chronic liver disease in many developed countries (1), and nonalcoholic steatohepatitis (NASH), the more severe histological form of NAFLD, is associated with an increased risk for the progression to cirrhosis in 20% of these patients (2). NAFLD also increases the cardiometabolic risk (3-5) and all-cause mortality (6, 7) in humans. It is presently regarded as the main cause of cryptogenic liver cirrhosis in the United States (8). During liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into activated myofibroblasts, which produce ␣-smooth muscle actin (␣-SMA) and become a major cell type in hepatic fibrogenesis (9, 10).Sirtuin 3 (SIRT3) is an NAD ϩ -dependent protein deacetylase predominantly localized in the mitochondrial matrix (11-13). SIRT3 is up-regulated during prolonged fasting or a calorierestricted diet and is thus involved in the metabolic regulation of obesity and diabetes (14 -16). Based on several recent studies, SIRT3 is a primary regulator of the acetylation of mitochondrial proteins and their biological activity (16 -19) and is associated with NAFLD (20 -22).Two studies yielded findings showing that SIRT 3 is a major physiological regulator of succinate dehydrogenase (SDH) activity (23, 24). SDH catalyzes the oxidation of succinate to fumarate, thereby decreasing SDH activity, resulting in increased succinate levels (25,26). The succinate receptor (also known as GPR91) is a G protein-coupled receptor expressed in various tissues, including the retina, live...

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“…They can modulate HSC response and vice versa through direct cell-cell and paracrine interactions [1,2,10,27]. They can modulate HSC response and vice versa through direct cell-cell and paracrine interactions [1,2,10,27].…”

Section: Discussionmentioning

confidence: 99%

“…This ratio was chosen according to data from the literature [10,11]. To block the IL-6 and TGF-β1 pathways, tocilizumab (Roche, Welwyn, UK) and anti-TGF-β1 (R&D Systems) were used at 10 μg/ml.…”

Section: Culture Conditionsmentioning

confidence: 99%

IL-17 and TNF-α co-operation contributes to the proinflammatory response of hepatic stellate cells

Beringer

Miossec

2019

Clinical and Experimental Immunology

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Hepatic stellate cells (HSCs) have a central role in liver inflammation and fibrosis by producing inflammatory and fibrotic mediators. Their activation is regulated through direct cell-cell interactions, but also through systemic and local effects of soluble factors such as cytokines. The effects of the proinflammatory cytokines interleukin (IL)-17 and tumor necrosis factor (TNF)-α and cell interactions with hepatocytes on HSC activation were assessed. Human HSC and HepaRG cells were exposed to IL-17 and/ or TNF-α. IL-17 and TNF-α contribution from immune cells was determined in a co-culture model with phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMC), HSC and/or hepatocytes. IL-17 enhanced TNF-α effects on the induction of IL-6, IL-1β, and the chemokine IL-8, chemokine (C-C motif) ligand 20 (CCL20) and monocyte chemoattractant protein-1 (MCP-1) expression/secretion in isolated HSC cultures. HSC-hepatocyte interactions did not enhance IL-6, IL-8 and CCL20 production compared to hepatocyte alone. However, HSC-hepatocyte interactions increased C-reactive protein expression. IL-17 and/or TNF-α had no direct profibrotic effects on collagen 1 α1, tissue inhibitor of matrix metalloproteinase (TIMP) and matrix metalloproteinase (MMP) 2 gene expression, whereas mRNA levels of MMP3, an enzyme involved in matrix destruction, were up-regulated in HSCs. The use of specific inhibitors of IL-17 and TNF-α indicated their contribution to the strong increase of IL-6 and IL-8 production induced by PBMC, HSC and/or hepatocyte interactions. As chronic liver inflammation leads to liver fibrosis, IL-17 and/or TNF-α neutralization can be of interest to control liver inflammation and therefore its effects on fibrosis.

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The interplay between hepatic stellate cells and hepatocytes in an in vitro model of NASH

Cited by 55 publications

References 30 publications

Human germline hedgehog pathway mutations predispose to fatty liver

Human germline hedgehog pathway mutations predispose to fatty liver

Sirtuin 3 (SIRT3) Regulates α-Smooth Muscle Actin (α-SMA) Production through the Succinate Dehydrogenase-G Protein-coupled Receptor 91 (GPR91) Pathway in Hepatic Stellate Cells

IL-17 and TNF-α co-operation contributes to the proinflammatory response of hepatic stellate cells

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