Dysregulations of UDP-glucuronosyltransferases in rats with valproic acid and high fat diet induced fatty liver

Abstract Both high fat diet (HFD) and valproic acid (VPA) interfere with mitochondrial β-oxidation of fatty acids, which subsequently triggers microvesicular fatty liver and hepatic dysfunction. UDP-glucuronosyltransferases, the major phase II drug metabolism enzymes, play a pivotal role in detoxifying various exogenous and endogenous compounds. This study aimed to investigate the dysregulation patterns of major UDP-glucuronosyltransferases (UGTs) induced by VPA and/or HFD. Biochemical and histopathological results showed that chronic treatments of VPA and HFD induced fatty liver and liver dysfunction in a synergistic manner. VPA upregulated the mRNA levels of UGT1A1, 1A6, 1A7, and UGT2B1. Notably, the protein expression and enzymatic activity of UGT1A6 were significantly increased in rats treated with HFD or VPA alone, and were further enhanced by HFD and VPA co-treatment. This dysregulation pattern was largely recapitulated in the in vitro HepG2 cells assay by using VPA and oleic acid treatment. Moreover, the induction of UGTs was accompanied by the increased expression of constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα). In line with the up-regulation of UGT1A1 and UGT1A6, urine recovery of VPA glucuronide (VPA-G) was sharply increased by VPA treatment, and the co-treatment of HFD further aggravated this change. Since VPA is necessarily prescribed for long-term and the prevalence of HFD life style nowadays, the combined effect of HFD and VPA on disturbing UGTs should take concerns in the clinics.