Frontiers in Endocrinology
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2021
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IF 5.555
Bai Yu,Du Qiang,Zhang Le,Li Ling,Wang Nana,Wu Bo,Li Ping,Li Ling
This study aims to investigate the effect of angiopoietin like 8 (ANGPTL8) on gestational diabetes mellitus (GDM) and insulin resistance (IR). The GDM model was induced by high fat diet in mice, and IR was observed. The expression and secretion of ANGPTL8 were promoted in placenta of GDM mice. IR was induced in trophoblast cell HTR-8/SVneo by treatment of high concentration of insulin, and the expression levels of ANGPTL8 were increased. Silencing of ANGPTL8 alleviated IR and decreased glucose uptake in HTR-8/SVneo cells. However, the inflammation and oxidative stress in IR cells were not restrained by ANGPTL8 knockdown. In addition, c-Jun N-terminal kinase (JNK) signaling was activated by IR, which was inhibited by silencing of ANGPTL8. The effect of ANGPTL8 knockdown on IR was attenuated by JNK antagonist, and aggravated by JNK agonist, suggesting that ANGPTL8 affected IR by regulating JNK signaling. In conclusion, we demonstrated that the silencing of ANGPTL8 ameliorated IR by inhibiting JNK signaling in trophoblast cells. These findings may provide novel insights for diagnosis and treatment of GDM in clinic.
研究领域:
内分泌学
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妇产科学
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分子生物学
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DOI
PubMed
高影响因子
Cardiovascular Diabetology
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2018
·Vol. 17
·期 1
·1-8
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IF 5.235
Luo Mengdie,Zhang Ziyu,Peng Yani,Wang Shuai,Peng Daoquan
Background It is well known that angiopoietin-like protein 8 (ANGPTL8) exerts its effects on lipid metabolism through the inhibition of lipoprotein lipase and subsequent elevation of plasma triglyceride. However, it is not clear whether ANGPTL8 could affect lipid metabolism via other pathways. The study was aimed to investigate the effects of ANGPTL8 on the function of high-density lipoprotein (HDL), which plays a protective role in atherosclerosis progression.Methods Two hundred and ten subjects were recruited. Plasma ANGPTL8 was measured by enzyme-linked immunosorbent assays. Cholesterol efflux capacity was chosen as the biomarker of HDL function and measured via H3-cholesterol loading THP-1 cell models.Results ANGPTL8 exhibited no significant difference between CAD group and nonCAD group, but ANGPTL8 in DM group was significantly higher than that in the nonDM group [568.3 (406.2–836.8) vs 458.2 (356.8–755.6), P = 0.023]. Compared to controls, subjects in CAD group and DM group exhibited significantly lower cholesterol efflux capacity [CAD: 14.58 ± 2.06 vs 12.51 ± 2.83%, P < 0.0001; DM: 13.62 ± 2.57 vs 12.34 ± 3.16%, P = 0.0099]. ANGPTL8 was inversely correlated with cholesterol efflux capacity (r = − 0.188, P < 0.01). Regression analysis revealed that plasma ANGPTL8 was an independent contributor to cholesterol efflux capacity (standardized β = − 0.143, P = 0.023).Conclusion ANGPTL8 presents a negative effect on HDL-mediated cholesterol efflux capacity.
研究领域:
医学
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生物化学
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DOI
PubMed
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BIOGERONTOLOGY
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2026
·Vol. 27
·期 5
·174
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IF 5.3
Chen Meijuan,Zhang Min,Mei Hanyi,Bai Xinyu,Wang Xiaoli,Tang Yijun,Jiang Hua,Zhang Lulu,Zhou Chunfang,Yuan Yahong
Hematopoiesis depends on the sustained function of hematopoietic stem and progenitor cells (HSPCs). However, aging progressively impairs HSPC function, contributing to immunosenescence, hematologic malignancies, and degenerative disorders. Therefore, elucidating the mechanisms underlying HSPC aging is essential for developing strategies to alleviate age-related dysfunction. Here, we identify angiopoietin-like 8 (ANGPTL8), a secreted glycoprotein known for its role in glucose and lipid metabolism, as a novel regulator of HSPC aging. Systemic ANGPTL8 knockout significantly attenuated senescence-associated phenotypes in multiple murine tissues. In vitro and in vivo analyses of proliferation, colony-forming capacity, mitochondrial membrane potential, senescence-associated secretory phenotype (SASP) expression, reactive oxygen species (ROS) accumulation, myeloid skewing, and early hematopoietic regeneration further demonstrated that ANGPTL8 promotes HSPC aging. Mechanistically, ANGPTL8 deficiency activated the PI3K/AKT signaling pathway, whereas a PI3K activator rescued the senescence effects induced by recombinant ANGPTL8 (rANGPTL8). Furthermore, co-immunoprecipitation (Co-IP) confirmed that rANGPTL8 directly interacts with the transmembrane receptor PirB. Recombinant PirB (rPirB) reduced the phosphorylation of PI3K/AKT, whereas PirB knockdown effectively blocked the inhibitory effect of rANGPTL8 on PI3K/AKT phosphorylation. Collectively, our findings suggest that ANGPTL8 drives HSPC aging primarily by suppressing the PI3K/AKT pathway via its receptor PirB, providing a new potential target to alleviate the aging of HSPCs.
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CELL DEATH AND DIFFERENTIATION
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2024
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IF 13.7
Yang Jing,Wan Shi-yuan,Song Qiu-yi,Xie Yun-hao,Wan Jun,Zhou Yi-hao,Zhang Zi-tong,Xiao Yu-shuo,Li Xi,Chen Hong,Liu Xin-ran,Xu Li,You Hui-juan,Hu De-sheng,Petersen Robert B.,Zhang Yong-hui,Zheng Ling,Zhang Yu,Huang Kun
Upon genotoxic stresses, cells employ various DNA damage responses (DDRs), including DNA damage repair or apoptosis, to safeguard genome integrity. However, the determinants among different DDRs choices are largely unknown. Here, we report angiopoietin-like protein 8 (ANGPTL8), a secreted regulator of lipid metabolism, localizes to the nucleus and acts as a dynamic switch that directs DDRs towards apoptosis rather than DNA repair after genotoxin exposure. ANGPTL8 deficiency alleviates DNA damage and apoptosis in cells exposed to genotoxins, as well as in the liver or kidney of mice injured by hepatic ischemia/reperfusion or cisplatin treatment. Mechanistically, ANGPTL8 physically interacts with Poly (ADP-ribose) polymerase 1 (PARP1), in a PARylation-independent manner, and reduces the fluidity of PARP1-DNA condensates, thereby enhancing the pro-apoptotic accumulation of PARP1 and PAR chains on DNA lesions. However, the transcription of ANGPTL8 is gradually decreased following genotoxin treatment, partly due to downregulation of CCAAT enhancer binding protein alpha (CEBPA), presumably to avoid further cytotoxicity. Together, we provide new insights by which genotoxic stress induced DDRs are channeled to suicidal apoptosis to safeguard genome integrity.
研究领域:
癌症生物学
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分子遗传学
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细胞生物学
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PubMed
高影响因子
BMC Pregnancy and Childbirth
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2026
·Vol. 26
·期 1
·363
·
IF 3.1
Xie Xinping,Yan Jianying,Chen Xiaoyun,He Lidan,Wu Jianbo,Lu Lin
Background Insulin resistance (IR) is a pivotal determinant in the pathophysiological processes underlying gestational diabetes mellitus (GDM). Angiopoietin-like protein 8 (ANGPTL8) exhibits an ambiguous influence on glucose metabolism in the onset and progression of GDM. However, the functions of ANGPTL8 in the metabolic profiles of insulin-resistant (IR) HepG2 cells, glucose tolerance in GDM mice, and the possible underlying mechanisms require further exploration. Methods ANGPTL8 knockout and over-expressing HepG2 cell lines were established. Glucose uptake capacity in three clones (wild-type, ANGPTL8 knockout, and over-expressing) of insulin-resistant HepG2 cells was detected. Proteomic analysis of the IR HepG2 cells identified a cluster of relevant signaling pathways, and the effect of ANGPTL8 on metabolomic changes was evaluated. The GDM model was induced by a high-fat diet (HFD) and intraperitoneal injection of Streptozotocin (STZ) in pregnant mice. An oral glucose tolerance test (OGTT) was performed in both GDM mice and ANGPTL8 over-expressing GDM mice. Results The PI3K/Akt signaling cascade was stimulated by insulin resistance, and this activation could be effectively suppressed by inhibitors targeting PI3K, Akt, and GSK-3β. HepG2 cells over-expressing ANGPTL8 and exposed to high insulin concentrations demonstrated a marked enhancement in glucose uptake capacity, as opposed to their wild-type counterparts or ANGPTL8 knockout cells under IR conditions. The most substantial down-regulation was observed in lactate and branched-chain amino acids (BCAAs), which exhibited a positive correlation with IR. Promoted translation of ANGPTL8 was found in the liver, pancreas, and placental tissues of GDM mice. Significantly better glucose tolerance was observed in GDM mice transfected with m-ANGPTL8 compared with those that were not. Furthermore, the activation of Akt was observed in the primary hepatocytes of ANGPTL8 over-expressing GDM mice. Conclusion Over-expression of ANGPTL8 may increase glucose uptake capacity and influence the metabolic profiles in IR HepG2 cells, enhancing the insulin-mediated activation of the PI3K/Akt/GSK-3β pathway. ANGPTL8 may improve glucose tolerance in GDM mice. These findings might contribute to a new understanding of the roles of ANGPTL8 in glucose metabolism during the onset and progression of insulin resistance, providing novel insights for the clinical therapy of GDM.
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