Intestinal peroxisome proliferator-activated receptor α-fatty acid-binding protein 1 axis modulates nonalcoholic steatohepatitis

Background and Aims Peroxisome proliferator-activated receptor alpha (PPAR alpha) regulates fatty acid transport and catabolism in liver. However, the role of intestinal PPAR alpha in lipid homeostasis is largely unknown. Here, intestinal PPAR alpha was examined for its modulation of obesity and NASH. Approach and Results Intestinal PPAR alpha was activated and fatty acid-binding protein 1 (FABP1) up-regulated in humans with obesity and high-fat diet (HFD)-fed mice as revealed by using human intestine specimens or HFD/high-fat, high-cholesterol, and high-fructose diet (HFCFD)-fed C57BL/6N mice and PPARA-humanized, peroxisome proliferator response element-luciferase mice. Intestine-specific Ppara or Fabp1 disruption in mice fed a HFD or HFCFD decreased obesity-associated metabolic disorders and NASH. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with fatty acid uptake assays in primary intestinal organoids revealed that intestinal PPAR alpha induced the expression of FABP1 that in turn mediated the effects of intestinal PPAR alpha in modulating fatty acid uptake. The PPAR alpha antagonist GW6471 improved obesity and NASH, dependent on intestinal PPAR alpha or FABP1. Double-knockout (Ppara/Fabp1(Delta IE)) mice demonstrated that intestinal Ppara disruption failed to further decrease obesity and NASH in the absence of intestinal FABP1. Translationally, GW6471 reduced human PPARA-driven intestinal fatty acid uptake and improved obesity-related metabolic dysfunctions in PPARA-humanized, but not Ppara-null, mice. Conclusions Intestinal PPAR alpha signaling promotes NASH progression through regulating dietary fatty acid uptake through modulation of FABP1, which provides a compelling therapeutic target for NASH treatment.