内分泌学
过氧化物酶体增殖物激活受体
内科学
脂肪酸
过氧化物酶体
生物
脂肪酸结合蛋白
脂肪肝
过氧化物酶体增殖物激活受体α
过氧化物酶体增殖物激活受体δ
核受体
受体
化学
生物化学
转录因子
医学
基因
疾病
作者
Tingting Yan,Yuhong Luo,Nana Yan,Keisuke Hamada,Nan Zhao,Yangliu Xia,Ping Wang,Changdong Zhao,Dan Qi,Shoumei Yang,Lulu Sun,Jie Cai,Qiong Wang,Changtao Jiang,Oksana Gavrilova,Kristopher W. Krausz,Daxesh P. Patel,Xiaoting Yu,Xuan Wu,Haiping Hao,Weiwei Liu,Aijuan Qu,Frank J. Gonzalez
出处
期刊:Hepatology
[Wiley]
日期:2022-05-15
卷期号:77 (1): 239-255
被引量:49
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI