RESUMEN
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.
Asunto(s)
Trastornos del Metabolismo de la Glucosa/complicaciones , Trastornos del Metabolismo de la Glucosa/metabolismo , Trastornos del Metabolismo de los Lípidos/complicaciones , Trastornos del Metabolismo de los Lípidos/metabolismo , Hepatopatías/complicaciones , Hepatopatías/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/genética , Animales , Dieta Alta en Grasa , Ácidos Grasos/metabolismo , Técnicas de Inactivación de Genes/métodos , Glucosa/metabolismo , Trastornos del Metabolismo de la Glucosa/genética , Células HEK293 , Hepatocitos/metabolismo , Humanos , Trastornos del Metabolismo de los Lípidos/genética , Hígado/metabolismo , Hepatopatías/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Transfección/métodos , Triglicéridos/metabolismoRESUMEN
PIWI-interacting RNAs (piRNAs) are a kind of non-coding small RNAs, which play a biological role by specifically binding to PIWI proteins. Studies have demonstrated that piRNAs play a significant role in germline cell growth by repressing transposable elements, especially in the regulation of DNA methylation. Recently increasing evidence revealed that piRNAs involved in the regulation of cell proliferation, apoptosis, and cycle; however, the mechanism of piRNAs is unclear. This review summarizes the research progress regarding the roles of piRNAs in the cell proliferation, apoptosis, and cycle.