posted on 2020-04-21, 17:01authored byAda AdminAda Admin, Zhenzhen Chen, Xiangyang Liu, Yanjin Luo, Junpei Wang, Yuhong Meng, Lei Sun, Yongsheng Chang, Qinghua Cui, Jichun Yang
Mitochondrial protein FAM3A suppresses hepatic
gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that
activates FAM3A expression, and evaluate its effect(s) on hyperglycemia and
steatosis. Drug-repurposing methodology predicted that antidepressive drug
doxepin was among the drugs that potentially activated FAM3A expression. Doxepin
was further validated to stimulate the translocation of transcription factor HNF4a from the cytoplasm into the nucleus, where it promoted FAM3A
transcription to enhance ATP synthesis, suppress gluconeogenesis and reduce
lipid deposition in hepatocytes. HNF4a antagonism or FAM3A deficiency blunted doxepin-induced suppression
on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated
hyperglycemia, steatosis and obesity in obese diabetic mice with upregulated
FAM3A expression in liver and brown adipose tissues. Notably, doxepin failed to
correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed
on HFD. Doxepin’s effects on ATP production, Akt activation, gluconeogenesis
and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In
conclusion, FAM3A is a therapeutical target for diabetes and steatosis. Antidepressive
drug doxepin activates FAM3A signaling pathways in liver and brown adipose
tissues to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin
might be preferentially recommended as
antidepressive drug in potential treatment of diabetic patients complicated
with depression.
Funding
This study was supported by grants from National Key Research Program of China (2017YFC0909600/2016YFC0903000), the Natural Science Foundation of China (81670748/81471035/81322011/81670462/81422006) and Beijing Natural Science Foundation (7171006)