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

Abstract

Non-alcoholic fatty liver disease (NAFLD) is currently one of the most common types of chronic liver injury. Elevated serum uric acid is a strong predictor of the development of fatty liver as well as metabolic syndrome. Here we demonstrate that uric acid induces triglyceride accumulation by SREBP-1c activation via induction of endoplasmic reticulum (ER) stress in hepatocytes. Uric acid-induced ER stress resulted in an increase of glucose-regulated protein (GRP78/94), splicing of the X-box-binding protein-1 (XBP-1), the phosphorylation of protein kinase RNA-like ER kinase (PERK), and eukaryotic translation initiation factor-2a (eIF-2a) in cultured hepatocytes. Uric acid promoted hepatic lipogenesis through overexpression of the lipogenic enzyme, acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1) via activation of SREBP-1c, which was blocked by probenecid, an organic anion transport blocker in HepG2 cells and primary hepatocytes. A blocker of ER stress, tauroursodeoxycholic acid (TUDCA), and an inhibitor of SREBP-1c, metformin, blocked hepatic fat accumulation, suggesting that uric acid promoted fat synthesis in hepatocytes via ER stress-induced activation of SREBP-1c. Uric acid-induced activation of NADPH oxidase preceded ER stress, which further induced mitochondrial ROS production in hepatocytes. These studies provide new insights into the mechanisms by which uric acid stimulates fat accumulation in the liver.

Niacin inhibits fat accumulation, oxidative stress, and inflammatory cytokine IL-8 in cultured hepatocytes: Impact on non-alcoholic fatty liver disease

“…Niacinmediated reduction in ROS was associated with significant inhibition of NADPH oxidase, a key enzyme involved in ROS production. Although NADPH oxidase is primarily located in hepatic Kupffer cells, hepatocytes have also been shown to exhibit NADPH activity and may participate in increased ROS production in hepatocytes [40][41][42][43]. Our findings suggest that niacin, at least in part, through inhibiting NADPH oxidase may decrease ROS generation in hepatocytes.…”

Uric Acid Induces Cardiomyocyte Apoptosis via Activation of Calpain-1 and Endoplasmic Reticulum Stress

“…Pretreatment with the calpain inhibitor CI-III mitigated UA-induced ER stress and subsequent apoptosis, while pretreatment with the ER stress inhibitor TUDCA did not significantly influence calpain-1 activity, indicating that UA induces cardiomyocyte apoptosis through activation of calpain-1 and ER stress and that calpain-1 is an upstream regulator of ER stress in the UA-induced effects in cardiomyocytes. * Other mechanisms of UA-induced ER stress have also reported [37, 38]. …”

Effect of uric acid on mitochondrial function and oxidative stress in hepatocytes

“…A previous study reported that mitochondrial stimulation resulted in hepatocyte damage, which, in turn, caused oxidative stress in hyperuricemic rats . Another study conducted in a UA-induced non-alcoholic fatty liver showed that uric acid induced ROS production in the mitochondria, which led to increased fat synthesis and triglyceride accumulation (Choi et al, 2014). However, the exact mechanism of the effect of UA on hepatocyte mitochondrial function remains unclear.…”