FAM3A mediates PPARγ's protection in liver ischemia-reperfusion injury by activating Akt survival pathway and repressing inflammation and oxidative stress

Chen, Zhenzhen; Wang, Junpei; Yang, Weili; Chen, Ji; Meng, Yuhuan; Geng, Bin; Cui, Qinghua; Yang, Jichun

doi:10.18632/oncotarget.17805

Cited by 32 publications

(36 citation statements)

References 45 publications

(54 reference statements)

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“…12,13 FAM3A is a target gene of peroxisome proliferator-activated receptor gamma (PPARγ), and it mediates the beneficial effects of PPARγ's activation on liver ischemia/reperfusion injury. 15,16 Beyond liver, FAM3A also regulates the functions of vascular smooth muscular cells (VSMCs) and adipocytes by modulating ATP-Akt pathways. 17,18 FAM3A also protects neuronal cells against apoptosis triggered by oxidative and endoplasmic reticulum (ER) stress.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Hypoxia is the lack of oxygen supply to tissues, which results in abnormal cell metabolism and function as well as pathological morphological alterations . The aetiology of hypoxia‐related diseases is complex and can be divided into four categories: hypoxic hypoxia induced by an arterial oxygen pressure drop, circulatory hypoxia caused by tissue blood flow reduction, hemic hypoxia induced by haemoglobin reduction and dysoxidative hypoxia caused by altered bio‐oxidation of tissues .…”

Section: Introductionmentioning

confidence: 99%

Endothelial microvesicles in hypoxic hypoxia diseases

Deng

Wang

et al. 2018

J Cellular Molecular Medi

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Hypoxic hypoxia, including abnormally low partial pressure of inhaled oxygen, external respiratory dysfunction‐induced respiratory hypoxia and venous blood flow into the arterial blood, is characterized by decreased arterial oxygen partial pressure, resulting in tissue oxygen deficiency. The specific characteristics include reduced arterial oxygen partial pressure and oxygen content. Hypoxic hypoxia diseases (HHDs) have attracted increased attention due to their high morbidity and mortality and mounting evidence showing that hypoxia‐induced oxidative stress, coagulation, inflammation and angiogenesis play extremely important roles in the physiological and pathological processes of HHDs‐related vascular endothelial injury. Interestingly, endothelial microvesicles (EMVs), which can be induced by hypoxia, hypoxia‐induced oxidative stress, coagulation and inflammation in HHDs, have emerged as key mediators of intercellular communication and cellular functions. EMVs shed from activated or apoptotic endothelial cells (ECs) reflect the degree of ECs damage, and elevated EMVs levels are present in several HHDs, including obstructive sleep apnoea syndrome and chronic obstructive pulmonary disease. Furthermore, EMVs have procoagulant, proinflammatory and angiogenic functions that affect the pathological processes of HHDs. This review summarizes the emerging roles of EMVs in the diagnosis, staging, treatment and clinical prognosis of HHDs.

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“…In cultured hepatocytes, ATPSβ overexpression similarly activated the PI3K-Akt pathway via ATP-P2 receptor-CaM signaling transduction independent of insulin [45]. Importantly, FAM3A and ATPSβ overexpression promoted the nuclear exclusion of FOXO1 in P2 receptor-dependent manner in cultured hepatocytes [45,46]. Collectively, these findings strongly suggested that the ATP-P2 receptor signaling pathway plays important roles in the regulation of Akt and FOXO1 activities, and subsequent glucose and lipid metabolism in hepatocytes independent of insulin.…”

Section: Fam3a Represses Hepatic Gluconeogenesis and Lipogenesismentioning

confidence: 80%

FAM3 gene family: A promising therapeutical target for NAFLD and type 2 diabetes

et al. 2018

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Non-alcoholic fatty liver disease (NAFLD) and diabetes are severe public health issues worldwide. The Family with sequence similarity 3 (FAM3) gene family consists of four members designated as FAM3A, FAM3B, FAM3C and FAM3D, respectively. Recently, there had been increasing evidence that FAM3A, FAM3B and FAM3C are important regulators of glucose and lipid metabolism. FAM3A expression is reduced in the livers of diabetic rodents and NAFLD patients. Hepatic FAM3A restoration activates ATP-P2 receptor-Akt and AMPK pathways to attenuate steatosis and hyperglycemia in obese diabetic mice. FAM3C expression is also reduced in the liver under diabetic condition. FAM3C is a new hepatokine that activates HSF1-CaM-Akt pathway and represses mTOR-SREBP1-FAS pathway to suppress hepatic gluconeogenesis and lipogenesis. In contrast, hepatic expression of FAM3B, also called PANDER, is increased under obese state. FAM3B promotes hepatic lipogenesis and gluconeogenesis by repressing Akt and AMPK activities, and activating lipogenic pathway. Under obese state, the imbalance among hepatic FAM3A, FAM3B and FAM3C signaling networks plays important roles in the pathogenesis of NAFLD and type 2 diabetes. This review briefly discussed the latest research progress on the roles and mechanisms of FAM3A, FAM3B and FAM3C in the regulation of hepatic glucose and lipid metabolism.

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FAM3A mediates PPARγ's protection in liver ischemia-reperfusion injury by activating Akt survival pathway and repressing inflammation and oxidative stress

Cited by 32 publications

References 45 publications

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

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

Endothelial microvesicles in hypoxic hypoxia diseases

FAM3 gene family: A promising therapeutical target for NAFLD and type 2 diabetes

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