Hepatic Klf10-Fh1 axis promotes exercise-mediated amelioration of NASH in mice.
Metabolism
; 155: 155916, 2024 Jun.
Article
in En
| MEDLINE
| ID: mdl-38615945
ABSTRACT
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Physical Conditioning, Animal
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Early Growth Response Transcription Factors
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Kruppel-Like Transcription Factors
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Non-alcoholic Fatty Liver Disease
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Fumarate Hydratase
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Liver
Limits:
Animals
Language:
En
Journal:
Metabolism
Year:
2024
Type:
Article