Repurposing doxepin to ameliorate steatosis and hyperglycemia by activating FAM3A signaling pathway

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.