RESUMEN
Exercise is an effective non-pharmacological strategy for the treatment of nonalcoholic steatohepatitis (NASH), but the underlying mechanism needs further investigation. Kruppel-like factor 10 (Klf10) is a transcriptional factor that is expressed in multiple tissues including liver, whose role in NASH is not well defined. In our study, exercise induces hepatic Klf10 expression through the cAMP/PKA/CREB pathway. Hepatocyte-specific knockout of Klf10 (Klf10LKO) increases lipid accumulation, cell death, inflammation and fibrosis in NASH diet-fed mice and reduces the protective effects of treadmill exercise against NASH, while hepatocyte-specific overexpression of Klf10 (Klf10LTG) works in concert with exercise to reduce NASH in mice. Mechanistically, Klf10 promotes the expression of fumarate hydratase 1 (Fh1), thereby reducing fumarate accumulation in hepatocytes. This decreases the trimethyl (me3) levels of histone 3 lysine 4 (H3K4me3) on lipogenic genes promoters to attenuate lipogenesis, thus ameliorating free fatty acids (FFAs)-induced hepatocytes steatosis, apoptosis, insulin resistance and blunting dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells. Therefore, by regulating the Fh1/fumarate/H3K4me3 pathway, Klf10 acts as a downstream effector of exercise to combat NASH.
Asunto(s)
Factores de Transcripción de la Respuesta de Crecimiento Precoz , Factores de Transcripción de Tipo Kruppel , Hígado , Enfermedad del Hígado Graso no Alcohólico , Condicionamiento Físico Animal , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/terapia , Enfermedad del Hígado Graso no Alcohólico/genética , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Condicionamiento Físico Animal/fisiología , Factores de Transcripción de la Respuesta de Crecimiento Precoz/metabolismo , Factores de Transcripción de la Respuesta de Crecimiento Precoz/genética , Hígado/metabolismo , Hepatocitos/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Masculino , Lipogénesis/genética , Lipogénesis/fisiologíaRESUMEN
Exercise is an effective non-pharmacological strategy for ameliorating nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism needs further investigation. Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) decreases basal metabolic rate of the mice and impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) increases basal metabolic rate of the mice and synergizes with exercise to ameliorate NAFLD. Mechanistically, Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD.
