Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress

Abstract

Background: Uric acid is an independent risk factor in fructose-induced fatty liver, but whether it is a marker or a cause remains unknown. Results: Hepatocytes exposed to uric acid developed mitochondrial dysfunction and increased de novo lipogenesis, and its blockade prevented fructose-induced lipogenesis. Conclusion: Rather than a consequence, uric acid induces fatty liver Significance: Hyperuricemic people are more prone to develop fructose-induced fatty liver.

Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes

“…26,27 ChREBP is a glucose-responsive basic/helix-loop-helix/leucine zipper transcription factor that is mainly expressed in liver and specifically binds to a carbohydrate response element containing E box. Activation of ChREBP was reported to occur with fructose, which could be mediated by fructose-induced uric acid generation; 13 however, we were not able to show a direct activation of ChREBP by uric acid. Despite an absence of uric acidinduced activation of ChREBP, our study showed that uric acid increased the cleavage of SREBP-1 into mature form and nuclear translocation.…”

“…We have previously reported mitochondrial oxidative stress by uric acid-activated ATP citrate lyase and FAS that led to de novo lipogenesis in liver. 13 In this manuscript, we have identified an additional mechanism whereby uric acid induces hepatic steatosis via ER stress.…”

“…11,12 Recent experimental studies have reported a benefit of hypouricemic therapy in ameliorating fat deposition in liver, [13][14][15] suggesting an etiological contribution of uric acid in the development of NAFLD or metabolic syndrome. In this study, we have demonstrated uric acidinduced fat accumulation in hepatocytes by enhancing the expression of lipogenic enzymes, which was associated with ER stress-mediated SREBP-1c cleavage and nuclear translocation.…”

“…13 Uric acid (46 mg/dl) increased H 2 O 2 production and NOX activity in HepG2 cells from 30 min (Figures 6a and b). Antioxidants, including NAC, DPI, and rotenone, blocked TG accumulation in HepG2 cells (Figure 6c), suggesting both NOX-dependent and mitochondria-mediated oxidative stress generated by uric acid were responsible for hepatic fat accumulation.…”

“…11 Additional studies have shown that elevated serum uric acid is an independent predictor of NAFLD. 12 Recently, uric acid has been shown to have direct effects to increase hepatic fat accumulation via a mechanism involving the induction of mitochondrial oxidative stress, 13 and lowering uric acid has been found to block hepatic fat accumulation in a variety of animal models. [13][14][15] However, the role of ER stress in uric acidmediated hepatic fat accumulation has not been previously examined.…”