Highlights
- •Antidepressant imipramine activates FAM3A-ATP-CaM-FOXA2-CPT2 pathway to ameliorate steatosis and hyperglycemia.
- •Imipramine also activates FAM3A pathway to stimulate UCP1 expression and thermogenesis in BAT.
- •Imipramine may be recommended in priority as antidepressant to depressive patients complicated with metabolic disorders.
Abstract
Mitochondrial FAM3A has been revealed to be a viable target for treating diabetes
and nonalcoholic fatty liver disease (NAFLD). However, its distinct mechanism in ameliorating
hepatic steatosis remained unrevealed. High-throughput RNA sequencing revealed that
carnitine palmityl transferase 2 (CPT2), one of the key enzymes for lipid oxidation,
is the downstream molecule of FAM3A signaling pathway in hepatocytes. Intensive study
demonstrated that FAM3A-induced ATP release activated P2 receptor to promote the translocation
of calmodulin (CaM) from cytoplasm into nucleus, where it functioned as a co-activator
of forkhead box protein A2 (FOXA2) to promote the transcription of CPT2, increasing
free fatty acid oxidation and reducing lipid deposition in hepatocytes. Furthermore,
antidepressant imipramine activated FAM3A-ATP-P2 receptor-CaM-FOXA2-CPT2 pathway to
reduce lipid deposition in hepatocytes. In FAM3A-deficient hepatocytes, imipramine
failed to activate CaM-FOXA2-CPT2 axis to increase lipid oxidation. Imipramine administration
significantly ameliorated hepatic steatosis, hyperglycemia and obesity of obese mice
mainly by activating FAM3A-ATP-CaM-FOXA2-CPT2 pathway in liver and thermogenesis in
brown adipose tissue (BAT). In FAM3A-deficient mice fed on high-fat-diet, imipramine
treatment failed to correct the dysregulated lipid and glucose metabolism, and activate
thermogenesis in BAT. In conclusion, imipramine activates FAM3A-ATP-CaM-FOXA2-CPT2
pathway to ameliorate steatosis. For depressive patients complicated with metabolic
disorders, imipramine may be recommended in priority as antidepressive drug.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: August 19, 2022
Accepted:
August 12,
2022
Received:
May 23,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
