Cyanidin‐3‐O‐glucoside improves non‐alcoholic fatty liver disease by promoting PINK1‐mediated mitophagy in mice

Abstract

Background and Purpose: Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism. Experimental Approach: Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 weeks. In vivo, recombinant adenoviruses and AAV8 were used for overexpression and knockdown of PTEN-induced kinase 1 (PINK1), respectively. AML-12 and HepG2 cells were used for the mechanism study. Key Results: C3G administration suppressed hepatic oxidative stress, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and steatosis and improved systemic glucose metabolism in mice with NAFLD. These effects of C3G were also observed in palmitic acid-treated AML-12 cells and hepatocytes from NAFLD patients. Mechanistic investigations revealed that C3G increased PINK1/Parkin expression and mitochondrial localization and promoted PINK1-mediated mitophagy to clear damaged mitochondria. Knockdown of hepatic PINK1 abolished the mitophagy-inducing effect of C3G, which blunted the beneficial effects of C3G on oxidative stress, NLRP3 inflammasome activation, hepatic steatosis and glucose metabolism. Conclusion and Implications: These results demonstrate that PINK1-mediated mitophagy plays an essential role in the ability of C3G to alleviate NAFLD and suggest that C3G may be a potential drug candidate for NAFLD treatment. 1 | INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide and is defined as the accumulation of fat in the liver in individuals who do not consume excessive alcohol. The global prevalence of non-alcoholic fatty liver disease is 25.24% and nonalcoholic fatty liver disease may progress to non-alcoholic steatohepatitis and cirrhosis or progress directly to hepatocellular carcinoma (Younossi et al., 2016). However, no pharmacological treatment approved by the US Food and Drug Administration is currently available.

Global ubiquitylation analysis of mitochondria in primary neurons identifies physiological Parkin targets following activation of PINK1

“…Activation of Parkin in neurons may also be associated with proximal signalling events independent of mitophagy and interestingly, several of the common neuronal sites we identified, occur on proteins involved in fatty acid oxidation and metabolism in the mitochondria including CPT1α, ACSL1, VDACs, CYB5R3 (Figure 2 and 3). Recently several in vivo physiological studies have suggested a link between fatty acid oxidation and mitophagy mechanisms in non-neuronal tissues (Shao et al, 2020, Li et al, 2020) and in future work it will be interesting to investigate whether Parkin-induced ubiquitylation of these proteins affects fatty acid metabolism at the molecular level in neurons.…”

Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk

“…Fat-induced liver damage is associated with inhibited mitophagy and following the mitochondria-mediated death of hepatocytes [ 33 ]. However, this also suggests several potential mitochondrial targets that can be used as a treatment to reduce inflammation via activated mitophagy, or as a prevention therapy to enhance mitophagy and protect against surplus lipid accumulation in the liver [ 34 , 35 ].…”

Phytochemicals: Targeting Mitophagy to Treat Metabolic Disorders

“…And whole-body insulin resistance and hepatic insulin resistance were observed in high-fat diet-fed liver-specific Parkin knockout mice ( Edmunds et al, 2020 ). In high-fat diet-fed mice, cyanidin-3-O-glucoside, a kind of anthocyanins mainly found in black rice, black beans and purple potatoes, significantly reduces body weight by activating PINK1-mediated mitophagy ( Li X. et al, 2020 ). Quercetin is proved to inhibit the body weight gain in high-fat diet-fed mice, simultaneously suppress the level of hepatic or serum cholesterol and triglyceride, and inhibit the expression of lipogenic gene fatty acid synthase (FAS) ( Liu et al, 2018 ).…”