Next Generation Sequencing Analysis of Pparafl/fl and Ppara?IE intestinal transcriptomes

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases globally and nonalcoholic steatohepatitis is its progressive stage with limited therapeutic options. Here a role for intestinal peroxisome proliferator-activated receptor a (PPARa)-fatty acid binding protein 1 (FABP1) in obesity-associated metabolic syndrome, fatty liver and nonalcoholic steatohepatitis via modulating dietary fat absorption was uncovered. Intestinal PPARa is highly activated accompanied by marked upregulation of FABP1 by high-fat diet (HFD) in mice and obese humans. Intestine-specific PPARa or FABP1 disruption in mice decreases HFD-induced obesity, fatty liver and nonalcoholic steatohepatitis and intestinal PPARa disruption fails to further decrease obesity and NASH. Chemical PPARa antagonism improves metabolic disorders depending on the presence of intestinal PPARa or FABP1. Translationally, GW6471 decreases human PPARa-driven intestinal fatty acid uptake and therapeutically improves obesity in PPARA-humanized, but not Ppara-null, mice. These results suggest that intestinal PPARa-FABP1 axis could be a therapeutic target for NASH. Overall design: Bulk RNA-seq of RNA isolated from the intestine of Chow- or HFD-fed Pparafl/fl and Ppara?IE mice.