Activation of mitophagy antagonizes high uric acid-induced hepatic lipid accumulation
Abstract
The rising prevalence of hyperuricemia associated with lifestyle changes has been confirmed as an independent risk factor for metabolic dysfunction-associated fatty liver disease. Mitochondria, as central regulators of lipid metabolism, maintain functional homeostasis through mitophagy, the selective removal of damaged or dysfunctional mitochondria. However, whether and how high uric acid (HUA) induces mitophagy and the mechanistic role of mitophagy in hyperuricemia-induced hepatic lipid metabolism disorders remain to be elucidated. Our study demonstrated that HUA induces hepatic fat accumulation and damaging mitochondria in primary mouse hepatocytes. Simultaneously, mitophagy was activated by HUA, evidenced by upregulated expression and phosphorylation of PINK1 and Parkin, enhanced LC3B-I to LC3B-II conversion, and enhanced TOM20-LC3B immunofluorescence colocalization. In urate oxidase gene knockout (Uox-KO) mice (a model of sustained hyperuricemia), we detected significantly elevated expression of mitophagy-related proteins in liver tissues, accompanied by marked lipid accumulation and inflammatory responses. Further studies demonstrated that HUA upregulates CD36 protein expression. CD36 knockdown alleviated lipid accumulation in primary mouse hepatocytes, whereas PINK1 knockdown exacerbated this effect through further CD36 upregulation. Notably, treatment with the mitophagy activator urolithin A significantly ameliorated hepatic lipid accumulation and inflammation in…
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