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Lab Invest. 2014 Oct;94(10):1114-25. doi: 10.1038/labinvest.2014.98. Epub 2014 Aug 11.

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

Author information

1
Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
2
Department of Biochemistry, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
3
Department of Molecular Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
4
Department of Life Sciences, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
5
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
6
The Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA.

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-2α (eIF-2α) 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.

PMID:
25111690
DOI:
10.1038/labinvest.2014.98
[Indexed for MEDLINE]
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