FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

Abstract

So far, the mechanism that links mitochondrial dysfunction to PDX1 inhibition in the pathogenesis of pancreatic β cell dysfunction under diabetic condition remains largely unclear. This study determined the role of mitochondrial protein FAM3A in regulating PDX1 expression in pancreatic β cells using gain‐ and loss‐of function methods in vitro and in vivo. Within pancreas, FAM3A is highly expressed in β, α, δ, and pp cells of islets. Islet FAM3A expression was correlated with insulin expression under physiological and diabetic conditions. Mice with specific knockout of FAM3A in islet β cells exhibited markedly blunted insulin secretion and glucose intolerance. FAM3A‐deficient islets showed significant decrease in PDX1 expression, and insulin expression and secretion. FAM3A overexpression upregulated PDX1 and insulin expressions, and augmented insulin secretion in cultured islets and β cells. Mechanistically, FAM3A enhanced ATP production to elevate cellular Ca2+ level and promote insulin secretion. Furthermore, FAM3A‐induced ATP release activated CaM to function as a co‐activator of FOXA2, stimulating PDX1 gene transcription. In conclusion, FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic β cells. Inhibition of FAM3A will trigger mitochondrial dysfunction to repress PDX1 and insulin expressions.

Dulaglutide Ameliorates Palmitic Acid-Induced Hepatic Steatosis by Activating FAM3A Signaling Pathway

“…FAM3A is a cytokine that is ubiquitously expressed in the tissues of human and rodents [ 14 ]. FAM3A controls the expression of pancreas/duodenum homeobox protein 1 (PDX1) and insulin and insulin secretion in the pancreatic beta cells under physiologica l and diabetic conditions [ 35 ]. Zhou et al [ 36 ] reported that the expression of FAM3A in human hepatocytes is increased by the PPARγ agonist, but not by PPARα and PPARδ agonists.…”

Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells

“…As described previously 24 , mice were anesthetized, and the upper part of the common bile duct near the hepatic portal vein was isolated and ligated. The duodenum was pulled with forceps and perfused with 3–5 mL of collagenase V [Sigma, 0.5 mg/mL in Hank’s Balanced Salt Solution (HBSS)] in the lower part of the common bile duct using an injection syringe.…”

“…In our previous study, we also showed that insulin secretion is significantly impaired in pancreatic β cell-specific knockout FAM3A mice. Mechanistically, FAM3A-induced ATP release activates the CaM-forkhead box protein A2 (FOXA2) pathway to directly induce the expression of pancreatic-duodenal homeobox 1 (PDX1), the key regulator of insulin gene expression, and β-cell growth and proliferation 24 . However, the role of intracellular ATP in FAM3A-induced PDX1 expression and insulin secretion remains unclear.…”

ATP Secretion and Metabolism in Regulating Pancreatic Beta Cell Functions and Hepatic Glycolipid Metabolism

“…In vitro , FAM3A overexpression enhances whereas FAM3A deficiency blunts ATP production and secretion, and GSIS in primary islets and β cell lines ( Yang et al, 2020 ; Yan et al, 2021 ). Mechanistically, FAM3A-promoted ATP release activates both P2X and P2Y receptors to increase cellular Ca 2+ , which stimulates the translocation of calmodulin (CaM) from cytoplasm into nucleus and directly interacts with forkhead box protein A2 (FOXA2) to augment its activation effect on the PDX-1 gene expression ( Yang et al, 2020 ). Upregulation of PDX-1 finally induces insulin gene expression and insulin secretion ( Yang et al, 2020 ).…”

“…Mechanistically, FAM3A-promoted ATP release activates both P2X and P2Y receptors to increase cellular Ca 2+ , which stimulates the translocation of calmodulin (CaM) from cytoplasm into nucleus and directly interacts with forkhead box protein A2 (FOXA2) to augment its activation effect on the PDX-1 gene expression ( Yang et al, 2020 ). Upregulation of PDX-1 finally induces insulin gene expression and insulin secretion ( Yang et al, 2020 ). Beyond extracellular ATP, intracellular ATP also contributed to FAM3A-induced PDX-1 upregulation and pancreatic β cell proliferation ( Yan et al, 2021 ).…”