Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor.
Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor.
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过氧化物酶体增殖物激活受体α作为转录抑制因子的机制研究。
DOI：
10.3389/fmed.2022.1060244
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发表时间：
2022
影响因子：
3.9
通讯作者：
中科院分区：
文献类型：
--
作者：
非酒精性脂肪性肝病（NAFLD）是最常见的肝脏疾病之一，世界人口的20-30%患有这种疾病。NAFLD的特征是肝脏中过量的脂质积聚，加重多种代谢综合征，如高脂血症、高胆固醇血症、高血压和2型糖尿病。大约20-30%的NAFLD病例进展为更严重的慢性肝炎，称为非酒精性脂肪性肝炎（NASH），显示肝功能恶化和肝纤维化，随后是肝硬化和癌症。先前的研究发现，几种代谢调节剂作为关键因素在疾病进展中发挥作用。过氧化物酶体增殖物激活受体α（Peroxisome proliferator-activated receptor alpha，PPARα）是肝脏脂质平衡的主要调节因子之一。PPARα在肝细胞中大量表达，是一种配体依赖性核受体，属于NR 1C核受体亚家族，协调脂质/葡萄糖代谢、炎症、细胞增殖和致癌作用。PPARα激动剂有望成为NASH治疗的新型处方药，其中一些（例如，Lanifibranor）目前正在进行临床试验。这些潜在的新药是基于对NAFLD和NASH相关的PPARα激活靶基因的认识而开发的。有趣的是，已知PPARα在激动剂治疗下抑制靶基因亚群的表达;然而，对PPARα介导的基因抑制的机制和这些基因的功能还不清楚。本文就PPARα抑制靶基因表达的机制及其在NALFD和NASH相关的肝脂代谢、肝纤维化和肝癌发生中的作用进行综述，并对PPARα的药物应用前景进行展望。
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent hepatic disorders that 20-30% of the world population suffers from. The feature of NAFLD is excess lipid accumulation in the liver, exacerbating multiple metabolic syndromes such as hyperlipidemia, hypercholesterolemia, hypertension, and type 2 diabetes. Approximately 20-30% of NAFLD cases progress to more severe chronic hepatitis, known as non-alcoholic steatohepatitis (NASH), showing deterioration of hepatic functions and liver fibrosis followed by cirrhosis and cancer. Previous studies uncovered that several metabolic regulators had roles in disease progression as key factors. Peroxisome proliferator-activated receptor alpha (PPARα) has been identified as one of the main players in hepatic lipid homeostasis. PPARα is abundantly expressed in hepatocytes, and is a ligand-dependent nuclear receptor belonging to the NR1C nuclear receptor subfamily, orchestrating lipid/glucose metabolism, inflammation, cell proliferation, and carcinogenesis. PPARα agonists are expected to be novel prescription drugs for NASH treatment, and some of them (e.g., Lanifibranor) are currently under clinical trials. These potential novel drugs are developed based on the knowledge of PPARα-activating target genes related to NAFLD and NASH. Intriguingly, PPARα is known to suppress the expression of subsets of target genes under agonist treatment; however, the mechanisms of PPARα-mediated gene suppression and functions of these genes are not well understood. In this review, we summarize and discuss the mechanisms of target gene repression by PPARα and the roles of repressed target genes on hepatic lipid metabolism, fibrosis and carcinogenesis related to NALFD and NASH, and provide future perspectives for PPARα pharmaceutical potentials.
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DOI：
10.1126/science.1198125
发表时间：
2011-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Feng D;Liu T;Sun Z;Bugge A;Mullican SE;Alenghat T;Liu XS;Lazar MA
通讯作者：
Lazar MA
影响因子：
4.8
作者：
Dowell, P;Peterson, VJ;Leid, M
通讯作者：
Leid, M
影响因子：
25.7
作者：
Bechmann, Lars P.;Vetter, Diana;Ishida, Junichi;Hannivoort, Rebekka A.;Lang, Ursula E.;Kocabayoglu, Peri;Fiel, M. Isabel;Munoz, Ursula;Patman, Gillian L.;Ge, Fengxia;Yakar, Shoshana;Li, Xiaosong;Agius, Loranne;Lee, Young-Min;Zhang, Weijia;Hui, Kei Yiu;Televantou, Despina;Schwartz, Gary J.;LeRoith, Derek;Berk, Paul D.;Nagai, Ryozo;Suzuki, Toru;Reeves, Helen L.;Friedman, Scott L.
通讯作者：
Friedman, Scott L.
影响因子：
15.9
作者：
Berthou, L;Duverger, N;Branellec, D
通讯作者：
Branellec, D
影响因子：
4.8
作者：
Bansal, Trisha;Chatterjee, Emeli;Sarkar, Sagartirtha
通讯作者：
Sarkar, Sagartirtha