Inhibition of SREBP-1c rescues hepatic CYP7B1 expression and bile acid synthesis in malnourished mice.

Abstract

Malnutrition decreases intestinal bile acids, resulting in inefficient nutrient absorption and impaired catch-up growth. Mechanisms by which bile acid depletion occurs in malnutrition are unknown. Using a mouse model of early-life malnutrition, we explored bile acid homeostasis, focusing on transcriptional repression of oxysterol 7α-hydroxylase (CYP7B1), a rate-limiting enzyme in the alternative pathway of bile acid biosynthesis, by sterol regulatory element-binding protein-1c (SREBP-1c), a master regulator of lipid metabolism. Mice were maintained on a low-protein, low-fat, or isocaloric control chow until 8 wk of age, when livers were harvested for proteome profiling, western blot, reverse transcription quantitative real-time PCR, and chromatin immunoprecipitation. Cultured hepatocytes and mice were treated with the SREBP-1c inhibitors fatostatin and betulin to determine whether this therapeutic strategy rescues CYP7B1 expression and bile acid synthesis in malnutrition. Malnutrition decreased the bile acid pool size and altered the expression of multiple hepatic cytochrome P450 enzymes, with profound depletion of CYP7B1, in males but not females. Malnutrition activated SREBP-1c and led to its enrichment at a Cyp7b1 gene regulatory region that featured loss of binding by the basal transcriptional activator specificity protein 1 (SP1). Treatment of cultured hepatocytes or malnourished mice with the SREBP-1c inhibitors fatostatin or betulin increased CYP7B1 expression. Both drugs rescued the bile acid pool size in malnourished mice. These results suggest that malnutrition impairs bile acid synthesis via transcriptional repression of Cyp7b1 by SREBP-1c. SREBP-1c inhibitors restore hepatic CYP7B1 expression and bile acid synthesis.NEW & NOTEWORTHY We applied liver proteomics to a unique mouse model of early-life malnutrition to reveal a novel mechanism of suppression of bile acid synthesis. Malnutrition activates the nuclear protein SREBP-1c, which displaces the transcriptional activator SP1 from the promoter of the Cyp7b1 gene. Two different SREBP-1c inhibitors rescue CYP7B1 expression in vitro and rescue the bile acid pool in malnourished mice. This discovery might facilitate novel adjunct therapies to enhance nutritional rehabilitation in malnourished children.