Liver X receptor in cooperation with SREBP‐1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver dysfunction and its incidence has increased markedly. However, the mechanisms involved in the pathogenesis of NAFLD in humans have not been thoroughly investigated. Sterol regulatory element binding protein (SREBP)-1c and carbohydrate responsive element binding protein (ChREBP) are transcriptional factors that regulate the expression of lipogenic genes, including acetyl-CoA carboxylases (ACCs) and fatty acid synthase (FAS). SREBP-1c and ChREBP are transactivated by liver X receptor (LXR), a nuclear receptor that regulates the metabolism of cholesterol and fatty acids. To understand the mechanisms involved in the pathogenesis of NAFLD, we investigated the transcriptional factors and lipogenic genes activated in the liver with NAFLD. Real-time PCR was carried out on liver biopsy samples from 20 NAFLD patients. The target genes studied were: ACC1, FAS, SREBP-1c, ChREBP, AMP-activated protein kinase (AMPK), and LXRalpha. LXRalpha, SREBP-1c, ACC1, and FAS were upregulated in NAFLD patients. Expression levels of LXR were four times greater than those of the controls and correlated significantly with SREBP-1c, but not with ChREBP, levels. These findings suggest that LXR acts as one of the main regulators of lipid metabolism by regulating SREBP-1c expression in NAFLD.