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.
Subject(s)
Early Growth Response Transcription Factors , Fumarate Hydratase , Kruppel-Like Transcription Factors , Liver , Non-alcoholic Fatty Liver Disease , Physical Conditioning, Animal , Animals , Male , Mice , Early Growth Response Transcription Factors/metabolism , Early Growth Response Transcription Factors/genetics , Hepatocytes/metabolism , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Lipogenesis/genetics , Lipogenesis/physiology , Liver/metabolism , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/therapy , Non-alcoholic Fatty Liver Disease/genetics , Physical Conditioning, Animal/physiology , Fumarate Hydratase/metabolismABSTRACT
Objective: To analyze the efficacy of using baseline calcitonin (bCtn) for auxiliary diagnosis of medullary thyroid cancer (MTC) in the hypercalcitoninemic population with thyroid nodules and to explore the relationship between preoperative levels of bCtn and carcinoembryonic antigen (CEA) and MTC staging. Methods: The clinical, pathological, imaging, and lab test data of 58 MTC patients and 84 non-MTC patients were retrospectively reviewed in the study. The patients were hospitalized at West China Hosptal, Sichuan University between 2011 and 2020. Receiver operating characteristic (ROC) curves were constructed to calculate the MTC diagnostic efficacy of bCtn and CEA. The differences in the preoperative bCtn and CEA levels of MTC patients with different primary tumor sites and regional lymph node involvement were compared. Results: The bCtn cutoff values were 31.54 pg/mL for men and 22.60 pg/mL for women for diagnosing MTC in the hypercalcitoninemic population with thyroid nodules. There were statistical differences in preoperative bCtn levels ( H=16.166, P=0.001) and in preoperative CEA levels ( H=9.447, P=0.024) in MTC patients of different T stages. There were statistical differences in preoperative bCtn levels ( H=7.919, P=0.019) and in preoperative CEA levels ( H=7.934, P=0.019) in MTC patients of different N stages. Conclusion: The best bCtn cutoff values for the diagnosis of MTC in the hypercalcitoninemic population with thyroid nodules and are 31.54 pg/mL for men and 22.60 pg/mL for women.
