FAM3A promotes vascular smooth muscle cell proliferation and migration and exacerbates neointima formation in rat artery after balloon injury.

The biological function of FAM3A, the first member of family with sequence similarity 3 (FAM3) gene family, remains largely unknown. This study aimed to determine its role in the proliferation and migration of vascular smooth muscle cells (VSMCs). Immunohistochemical staining revealed that FAM3A protein is expressed in the tunica media of rodent arteries, and its expression is reduced with an increase in prostaglandin E receptor 2 (EP2) expression after injury. In vitro, FAM3A overexpression promotes proliferation and migration of VSMCs, whereas FAM3A silencing inhibits these processes. In vivo, FAM3A overexpression results in exaggerated neointima formation of rat carotid artery after balloon injury. FAM3A activates Akt in a PI3K-dependent manner. In contrast, FAM3A induces ERK1/2 activation independent of PI3K. FAM3A protein is subcellularly located in mitochondria, where it affects ATP production and release. Activation of EP2 represses FAM3A expression, leading to impaired ATP production and release in VSMCs. FAM3A-induced activation of Akt and ERK1/2 pathways, proliferation and migration of VSMCs are inhibited by P2 receptor antagonist suramin. Furthermore, inhibition or knockdown of P2Y1 receptor inihibits FAM3A-induced proliferation and migration of VSMCs. In conclusion, FAM3A promotes proliferation and migration of VSMCs via P2Y1 receptor-mediated activation of Akt and ERK1/2 pathways. In injured vessels, FAM3A was repressed by upregulated EP2 expression, leading to the attenuation of ATP-P2Y1 receptor signaling, which is beneficial for preventing excessive proliferation and migration of VSMCs.

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 HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α 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 (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. 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 therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression.

Comparison Analysis of Dysregulated LncRNA Profile in Mouse Plasma and Liver after Hepatic Ischemia/Reperfusion Injury.

Long noncoding RNAs (LncRNAs) have been believed to be the major transcripts in various tissues and organs, and may play important roles in regulation of many biological processes. The current study determined the LncRNA profile in mouse plasma after liver ischemia/reperfusion injury (IRI) using microarray technology. Microarray assays revealed that 64 LncRNAs were upregulated, and 244 LncRNAs were downregulated in the plasma of liver IRI mouse. Among these dysregulated plasma LncRNAs, 59-61% were intergenic, 22-25% were antisense overlap, 8-12% were sense overlap and 6-7% were bidirectional. Ten dysregulated plasma LncRNAs were validated by quantitative PCR assays, confirming the accuracy of microarray analysis result. Comparison analysis between dysregulated plasma and liver LncRNA profile after liver IRI revealed that among the 308 dysregulated plasma LncRNAs, 245 LncRNAs were present in the liver, but remained unchanged. In contrast, among the 98 dysregulated liver LncRNAs after IRI, only 19 were present in the plasma, but remained unchanged. LncRNA AK139328 had been previously reported to be upregulated in the liver after IRI, and silencing of hepatic AK139328 ameliorated liver IRI. Both microarray and RT-PCR analyses failed to detect the presence of AK139328 in mouse plasma. In summary, the current study compared the difference between dysregulated LncRNA profile in mouse plasma and liver after liver IRI, and suggested that a group of dysregulated plasma LncRNAs have the potential of becoming novel biomarkers for evaluation of ischemic liver injury.