PPARα激动剂治疗非酒精性脂肪性肝病的研究进展

摘要/Abstract

摘要： 非酒精性脂肪性肝病(NAFLD)是目前全球最主要的慢性肝病,已成为我国面临的严重公共健康问题,其中约20%患者为非酒精性脂肪性肝炎(NASH),有可能进展为肝硬化甚至肝癌。目前主要以生活方式干预为主,尚无特效药物进行治疗。过氧化物酶体增殖物激活受体α(PPARα)及其配体参与调节糖脂代谢和能量代谢,PPARα激动剂对NAFLD患者肝脏脂质蓄积、肝脏炎症有潜在治疗作用,但临床效果并不显著,可能与PPARα具有组织特异性有关。故本文对PPARα参与疾病进展机制以及相关药物治疗的最新研究作一概述。

王资隆, 饶慧瑛. PPARα激动剂治疗非酒精性脂肪性肝病的研究进展[J]. 肝脏, 2023, 28(4): 396-397.

参考文献

[1] Powell EE, Wong VW,Rinella M. Non-alcoholic fatty liver disease. Lancet,2021,397:2212-2224.
[2] Zhou J,Zhou F, Wang W. et al. Epidemiological Features of NAFLD From 1999 to 2018 in China. Hepatology, 2020,71:1851-1864.
[3] Dubois V, Eeckhoute J, Lefebvre P, et al. Distinct but complementary contributions of PPAR isotypes to energy homeostasis. J Clin Invest, 2017, 127:1202-1214.
[4] Kersten S, Stienstra R. The role and regulation of the peroxisome proliferator activated receptor alpha in human liver. Biochimie,2017,136:75-84,
[5] Mahmoudi A, Jamialahmadi T, Johnston TP,et al. Impact of fenofibrate on NAFLD/NASH: A genetic perspective. Drug Discov Today,2022,27:2363-2372.
[6] Korbecki J, Bobiński R, Dutka M. Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflamm Res, 2019, 68:443-458.
[7] Francque S, Verrijken A, Caron S, et al. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol. 2015,63:164-173.
[8] Stec DE, Gordon DM, Hipp JA, et al. Loss of hepatic PPARα promotes inflammation and serum hyperlipidemia in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol, 2019, 317:R733-R745.
[9] Smati S, Polizzi A, Fougerat A, et al. Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target. Gut, 2022,71:807-821.
[10] Stojanovi? O, Altirriba J, Rigo D, et al. Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα. Nat Commun,2021,12:7031.
[11] Yoo J, Jeong IK, Ahn KJ, et al. Fenofibrate, a PPARα agonist, reduces hepatic fat accumulation through the upregulation of TFEB-mediated lipophagy. Metabolism,2021,120:154798.
[12] Sharpton SR, Schnabl B, Knight R, et al. Current Concepts, Opportunities, and Challenges of Gut Microbiome-Based Personalized Medicine in Nonalcoholic Fatty Liver Disease. Cell Metab,2021,33:21-32.
[13] Yan T, Luo Y, Yan N, et al. Intestinal peroxisome proliferator-activated receptor α-fatty acid-binding protein 1 axis modulates nonalcoholic steatohepatitis. Hepatology,2023,77:239-255.
[14] Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a New Selective PPARα Modulator: Drug Concept and Its Clinical Applications for Dyslipidemia and Metabolic Diseases. Curr Atheroscler Rep,2020,22:5.
[15] Sasaki Y, Asahiyama M, Tanaka T, et al. Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content. Sci Rep, 2020,10:7818.
[16] Nakajima A, Eguchi Y, Yoneda M, et al. Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), versus placebo in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther,2021,54:1263-1277.
[17] Jain MR, Giri SR, Bhoi B, et al. Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int,2018,38:1084-1094.
[18] Gawrieh S, Noureddin M, Loo N,et al. Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial. Hepatology,2021,74:1809-1824.
[19] Siddiqui MS, Idowu MO, Parmar D, et al. A Phase 2 Double Blinded, Randomized Controlled Trial of Saroglitazar in Patients With Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol, 2021,19:2670-2672.
[20] Møllerhøj MB, Veidal SS, Thrane KT, et al. Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH. Clin Transl Sci,2022,15:1167-1186.
[21] Boyer-Diaz Z, Aristu-Zabalza P, Andrés-Rozas M,et al. Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease. J Hepatol,2021,74:1188-1199.