Farnesoid X Receptor Deficiency Induces Hepatic Lipid and Glucose Metabolism Disorder via Regulation of Pyruvate Dehydrogenase Kinase 4

作者：Wenyi Deng, Wenjing Fan, Tingting Tang, Hengquan Wan, Simin Zhao, Yao Tan, Kwabena Agyare Oware, Jieqiong Tan, Jiequn Li, Stanley Qu · 发表于：Oxidative Medicine and Cellular Longevity · 年份：2022 · DOI：10.1155/2022/3589525 · 被引用次数：23 · 研究领域：Drug Transport and Resistance Mechanisms、Liver Disease Diagnosis and Treatment、Liver Diseases and Immunity

Farnesoid X receptors (FXR) are bile acid receptors that play roles in lipid, glucose, and energy homeostasis. Synthetic FXR‐specific agonists have been developed for treating nonalcoholic fatty liver disease (NAFLD) patients. However, the detailed mechanism remains unclear. To investigate the effects of FXR on NAFLD and the possible mechanism, FXR‐null mice were fed either a normal or a high‐fat diet. The FXR‐null mice developed hepatomegaly, steatosis, accumulation of lipid droplets in liver cells, glucose metabolism disorder, and elevated serum lipid levels. Transcriptomic results showed increased expression of key lipid synthesis and glucose metabolism‐related proteins. We focused on pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme involved in the regulation of glucose and fatty acid (FA) metabolism and homeostasis. Subsequently, we confirmed an increase in PDK4 expression in FXR knockout cells. Moreover, inhibition of PDK4 expression alleviated lipid accumulation in hepatocytes caused by FXR deficiency in vivo and in vitro . Our results identify FXR as a nuclear transcription factor that regulates glucose and lipid metabolism balance through PDK4, providing further insights into the mechanism of FXR agonists in the treatment of metabolic diseases.