Uric Acid Regulates Hepatic Steatosis and Insulin Resistance Through the NLRP3 Inflammasome-Dependent Mechanism

J Hepatol. 2016 Apr;64(4):925-32. doi: 10.1016/j.jhep.2015.11.022. Epub 2015 Nov 27.

Abstract

Background & aims: Hyperuricemia significantly increases risk of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. However, the mechanisms responsible for this association are as yet unclear. This study aimed to investigate the effects and underlying mechanisms of uric acid on development of NAFLD and insulin resistance.

Methods: We initially analyzed the impact of uric acid on the development of hepatic steatosis and insulin resistance in mice and in two cell models, HepG2 and L02. Subsequently, we studied the role of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in uric acid-induced fat accumulation and insulin signaling impairment.

Results: We found that uric acid directly induces hepatocyte fat accumulation, insulin resistance, and insulin signaling impairment both in vivo and in vitro. We also found that uric acid-induced NLRP3 inflammasome activation, whereas lowering uric acid by allopurinol inhibited NLRP3 inflammasome activation in a high fat diet mouse model of NAFLD. Moreover, knocking down NLRP3 expression significantly attenuated uric acid-induced fat accumulation both in HepG2 cells and L02 cells. Knocking down NLRP3 expression also rescued uric acid-induced insulin signaling impairment in both cell types.

Conclusions: Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome. Uric acid may be a new therapeutic target for NAFLD and insulin resistance.

Keywords: Fatty liver; Hyperuricemia; Insulin resistance; NLRP3 inflammasome; Uric acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / physiology
  • Animals
  • Fatty Liver / chemically induced*
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Humans
  • Inflammasomes / physiology*
  • Insulin Resistance*
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / drug effects
  • NLR Family, Pyrin Domain-Containing 3 Protein / physiology*
  • Reactive Oxygen Species / metabolism
  • Uric Acid / pharmacology*

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species
  • Uric Acid
  • AMP-Activated Protein Kinases