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

Abstract

Background and Aims Peroxisome proliferator‐activated receptor α (PPARα) regulates fatty acid transport and catabolism in liver. However, the role of intestinal PPARα in lipid homeostasis is largely unknown. Here, intestinal PPARα was examined for its modulation of obesity and NASH. Approach and Results Intestinal PPARα 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 PPARα induced the expression of FABP1 that in turn mediated the effects of intestinal PPARα in modulating fatty acid uptake. The PPARα antagonist GW6471 improved obesity and NASH, dependent on intestinal PPARα or FABP1. Double‐knockout (Ppara/Fabp1 ΔIE) 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 PPARα signaling promotes NASH progression through regulating dietary fatty acid uptake through modulation of FABP1, which provides a compelling therapeutic target for NASH treatment.

Per- and Polyfluoroalkyl Substances (PFASs) Impair Lipid Metabolism in Rana nigromaculata: A Field Investigation and Laboratory Study

“…This coincides with what was also found in the previous studies in mice. , In addition, coexposure of PFASs with GW6471 and SR9243 significantly alleviated the increase in gene expression, HSI value, and TG content induced by PFAS exposure (Figures J,K and S15). It has been reported that GW6471 and SR9243 alleviated high-fat diet-induced TG increase in mice. , In this study, the antagonists of PPARα and LXRα blocked PFAS-induced lipid accumulation, which provided effective evidence that lipid metabolism disorders induced by PFASs were mediated via the activation of PPARα and LXRα.…”

“…It has been reported that GW6471 and SR9243 alleviated high-fat diet-induced TG increase in mice. 63,64 In this study, the antagonists of PPARα and LXRα blocked PFAS-induced lipid accumulation, which provided effective evidence that lipid metabolism disorders induced by PFASs were mediated via the activation of PPARα and LXRα.…”

The role of hepatic microenvironment in hepatic fibrosis development

“…GW4064 may also inhibit the development of liver fibrosis by inhibiting HSC activation [ 40 ]. Peroxisome proliferator-activated receptor (PPAR) regulates fatty acid metabolism in the liver, and recent studies have demonstrated that PPARα antagonist GW6471 can improve NASH [ 41 ]. Other studies have demonstrated that lipid-regulating drugs fenofibrate and ciprofibrate can reduce pulmonary fibrosis, collagen production, and myofibroblast differentiation in mice [ 42 , 43 ].…”

Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor

“…PPARα activation could, therefore, be a primary pharmaceutical target (8). PPARα agonists also repress target genes (9)(10)(11) but the contribution of these "repressed target genes" to NAFLD and NASH and the mechanisms involved are not well understood. In this review, we focus on the target genes repressed by PPARα and the repression mechanisms elucidated hitherto, and discuss the potential significance of PPARα as a transcriptional suppressor.…”