Hepatic-specific activation of peroxisome proliferator-activated receptor γ coactivator-1β protects against steatohepatitis

Bellafante, Elena; Murzilli, Stefania; Salvatore, Lorena; Latorre, Daniela; Villani, Gaetano; Moschetta, Antonio

doi:10.1002/hep.26222

Cited by 47 publications

(59 citation statements)

References 33 publications

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“…A growing body of data shows a biological role of miR-378a-3p in a variety of diseases [27,28]. In cancer, miR-378a suppresses the growth of hepatitis B virus-related hepatocellular carcinoma by targeting the insulin-like growth factor 1 receptor [27].…”

Section: Discussionmentioning

confidence: 99%

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Fan

Chen

et al. 2016

Cell Physiol Biochem

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Background/Aims: Wnt/β-catenin pathway is involved in liver fibrosis and microRNAs (miRNAs) are considered as key regulators of the activation of hepatic stellate cells (HSCs). A recent study showed the protective role of miR-378a-3p against cardiac fibrosis. However, whether miR-378a-3p suppresses Wnt/β-catenin pathway in liver fibrosis is largely unknown. Methods: miR-378a-3p expression was detected in carbon tetrachloride-induced liver fibrosis and activated HSCs. Effects of miR-378a-3p overexpression on HSC activation and Wnt/β-catenin pathway were analyzed. Bioinformatic analysis was employed to identify the potential targets of miR-378a-3p. Serum miR-378a-3p expression was analyzed in patients with cirrhosis. Results: Reduced miR-378a-3p expression was observed in the fibrotic liver tissues and activated HSCs. Up-regulation of miR-378a-3p inhibited HSC activation including cell proliferation, α-smooth muscle actin (α-SMA) and collagen expression. Moreover, miR-378a-3p overexpression resulted in Wnt/β-catenin pathway inactivation. Luciferase reporter assays demonstrated that Wnt10a, a member of Wnt/β-catenin pathway, was confirmed to be a target of miR-378a-3p. By contrast, miR-378a-3p inhibitor contributed to HSC activation, with an increase in cell proliferation, α-SMA and collagen expression. But all these effects were blocked down by silencing of Wnt10a. Notably, sera from patients with cirrhosis contained lower levels of miR-378a-3p than sera from healthy controls. Receiver operating characteristic curve analysis suggested that serum miR-378a-3p differentiated liver cirrhosis patients from healthy controls, with an area under the curve of ROC curve of 0.916. Conclusion: miR-378a-3p suppresses HSC activation, at least in part, via targeting of Wnt10a, supporting its potential utility as a novel therapeutic target for liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a

Fan

Chen

et al. 2016

Cell Physiol Biochem

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“…PGC-1β and transducin beta-like 1 (TBL) also serve as PPARα coactivators. Hepatocyte-specific overexpression of PGC-1β increases the expression of β oxidative genes and protects PGC-1β transgenic mice from diet-induced steatosis (12). Knockdown of TBL1 or its partner TBLR1 in the liver inhibits PPARα activity, decreases β oxidation and ketogenesis, and promotes hepatic steatosis (117).…”

Section: Liver Fatty Acid Metabolismmentioning

confidence: 99%

Energy Metabolism in the Liver

Rui

2014

Comprehensive Physiology

1,605

1,282

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The liver is an essential metabolic organ, and its metabolic activity is tightly controlled by insulin and other metabolic hormones. Glucose is metabolized into pyruvate through glycolysis in the cytoplasm, and pyruvate is completely oxidized to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and cholesterol esters in hepatocytes, and these complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as VLDL particles. In the fasted state, the liver secretes glucose through both breakdown of glycogen (glycogenolysis) and de novo glucose synthesis (gluconeogenesis). During pronged fasting, hepatic gluconeogenesis is the primary source of endogenous glucose production. Fasting also promotes lipolysis in adipose tissue to release nonesterified fatty acids which are converted into ketone bodies in the liver though mitochondrial β oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver metabolic processes are tightly regulated by neuronal and hormonal systems. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis, but suppresses gluconeogenesis; glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze the rate-limiting steps of liver metabolic processes, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases (NAFLD).

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“…To better understand the contributions of either of these isoforms to phenotype, a liver-specific double-KO mouse model should be analyzed. A PGC-1␤ liver-specific overexpression model under the control of apolipoprotein E promoter has shown that PGC-1␤ overexpression protects against steatohepatitis through increased oxidative metabolism, ␤ oxidation and triglyceride secretion [114].…”

Section: Pgc-1α In Livermentioning

confidence: 99%