PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling

Ma, Ning; Wang, Yikang; Xu, Sheng; Ni, Qian‐Zhi; Zheng, Qian-Wen; Cao, Hui‐Jun; Jiang, Hao; Zhang, Feng-Kun; Yuan, Yang; Zhang, Er‐Bin; Chen, Tianwei; Ji, Xia; Ding, Xue; Chen, Zhenhua; Zhang, Xiuping; Wang, Kang; Cheng, Shuqun; Qiu, Lin; Li, Zhigang; Yu, Yongchun; Wang, Xiaofan; Zhou, Bin; Li, Jingjing; Xie, Dong

doi:10.1038/s41467-021-23285-8

Cited by 30 publications

(16 citation statements)

References 44 publications

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“…The protocol used for western blotting was described in previous report ( 24 ). The membranes were first probed with GRB10 (#3702) and GAPDH (#5174S) primary antibodies purchased from Cell Signaling Technology (CST).…”

Section: Methodsmentioning

confidence: 99%

GRB10 rs1800504 Polymorphism Is Associated With the Risk of Coronary Heart Disease in Patients With Type 2 Diabetes Mellitus

Yang

Qiu

Meng

et al. 2021

Front. Cardiovasc. Med.

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Diabetic vascular complications are one of the main causes of death and disability. Previous studies have reported that genetic variation is associated with diabetic vascular complications. In this study, we aimed to investigate the association between GRB10 polymorphisms and susceptibility to type 2 diabetes mellitus (T2DM) vascular complications. Eight single nucleotide polymorphisms (SNPs) in the GRB10 gene were genotyped by MassARRAY system and 934 patients with type 2 diabetes mellitus (T2DM) were included for investigation. We found that GRB10 rs1800504 CC+CT genotypes were significantly associated with increased risk of coronary heart disease (CHD) compared with TT genotype (OR = 2.24; 95%CI: 1.36–3.70, p = 0.002). Consistently, levels of cholesterol (CHOL) (CC+CT vs. TT, 4.44 ± 1.25 vs. 4.10 ± 1.00 mmol/L; p = 0.009) and low density lipoprotein cholesterin (LDL-CH) (CC+CT vs. TT, 2.81 ± 1.07 vs. 2.53 ± 0.82 mmol/L; p = 0.01) in T2DM patients with TT genotype were significant lower than those of CC+CT genotypes. We further validated in MIHA cell that the total cholesterol (TC) level in GRB10-Mut was significantly reduced compared with GRB10-WT; p = 0.0005. Likewise, the reversed palmitic acid (PA) induced lipid droplet formation in GRB10-Mut was more effective than in GRB10-WT. These results suggest that rs1800504 of GRB10 variant may be associated with the blood lipids and then may also related to the risk of CHD in patients with T2DM.

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Section: Methodsmentioning

confidence: 99%

GRB10 rs1800504 Polymorphism Is Associated With the Risk of Coronary Heart Disease in Patients With Type 2 Diabetes Mellitus

Yang

Qiu

Meng

et al. 2021

Front. Cardiovasc. Med.

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“…Pancreatic progenitor cell differentiation and proliferation factors regulate mTORC1 signaling in lipid metabolism; specifically, these processes and factors inhibit mTORC1 activity by blocking the decrease in Raptor ubiquitination, thereby inhibiting hepatic steatosis [ 43 ]. In this previous study, the relationship among Raptor, mTOR structure, and NAFLD-related lipid metabolism was not explored at the level of the overall mTORC1 structure.…”

Section: Mtor Regulates Liver Lipid Metabolism Through Srebpsmentioning

confidence: 99%

mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease

Feng

Qiu

Zhou

et al. 2022

IJMS

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The global prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, yet effective treatments are lacking due to the complex pathogenesis of this disease. Although recent research has provided evidence for the “multiple strikes” theory, the classic “two strikes” theory has not been overturned. Therefore, there is a crucial need to identify multiple targets in NAFLD pathogenesis for the development of diagnostic markers and targeted therapeutics. Since its discovery, the mechanistic target of rapamycin (mTOR) has been recognized as the central node of a network that regulates cell growth and development and is closely related to liver lipid metabolism and other processes. This paper will explore the mechanisms by which mTOR regulates lipid metabolism (SREBPs), insulin resistance (Foxo1, Lipin1), oxidative stress (PIG3, p53, JNK), intestinal microbiota (TLRs), autophagy, inflammation, genetic polymorphisms, and epigenetics in NAFLD. The specific influence of mTOR on NAFLD was hypothesized to be divided into micro regulation (the mechanism of mTOR’s influence on NAFLD factors) and macro mediation (the relationship between various influencing factors) to summarize the influence of mTOR on the developmental process of NAFLD, and prove the importance of mTOR as an influencing factor of NAFLD regarding multiple aspects. The effects of crosstalk between mTOR and its upstream regulators, Notch, Hedgehog, and Hippo, on the occurrence and development of NAFLD-associated hepatocellular carcinoma are also summarized. This analysis will hopefully support the development of diagnostic markers and new therapeutic targets in NAFLD.

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“…After cleavage in the endoplasmic reticulum, SREBP1 enters the nucleus and binds to a specific DNA sequence to activate the transcription of the lipogenic genes acetyl-CoA carboxylase alpha (ACACA), fatty acid synthase (FASN) and SCD1 [ 11 ]. The available data increasingly demonstrates that the mechanistic target of rapamycin (mTOR) is responsible for the activation of SREBP1 and lipid synthesis in the presence of cell differentiation and proliferation factors [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 promotes SCD1 expression via the PI3K-Akt-mTOR-SREBP1 signaling pathway in lung fibroblasts

et al. 2023

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Background Lung fibroblast activation is associated with airway remodeling during asthma progression. Stearoyl-CoA desaturase 1 (SCD1) plays an important role in the response of fibroblasts to growth factors. This study aimed to explore the effects of SCD1 on fibroblast activation induced by transforming growth factor-β1 (TGF-β1) and the role of the phosphatidylinositol-3-kinase-AKT serine-threonine protein kinase-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway on the regulation of SCD1 expression in airway remodeling. Methods Female C57BL/6 mice were sensitized and challenged with house dust mites to generate a chronic asthma model. The inhibitor of SCD1 was injected i.g. before each challenge. The airway hyper-responsiveness to methacholine was evaluated, and airway remodeling and airway inflammation were assessed by histology. The effects of SCD1 on fibroblast activation were evaluated in vitro using an SCD1 inhibitor and oleic acid and via the knockdown of SCD1. The involvement of the PI3K-Akt-mTOR-sterol regulatory element-binding protein 1 (SREBP1) pathway in lung fibroblasts was investigated using relevant inhibitors. Results The expression of SCD1 was increased in fibroblasts exposed to TGF-β1. The inhibition of SCD1 markedly ameliorated airway remodeling and lung fibroblast activation in peripheral airways. The knockdown or inhibition of SCD1 resulted in significantly reduced extracellular matrix production in TGF-β1-treated fibroblasts, but this effect was reversed by the addition of exogenous oleic acid. The PI3K-Akt-mTOR-SREBP1 pathway was found to be involved in the regulation of SCD1 expression and lung fibroblast activation. Conclusions The data obtained in this study indicate that SCD1 expression contributes to fibroblast activation and airway remodeling and that the inhibition of SCD1 may be a therapeutic strategy for airway remodeling in asthma.

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PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling

Cited by 30 publications

References 44 publications

GRB10 rs1800504 Polymorphism Is Associated With the Risk of Coronary Heart Disease in Patients With Type 2 Diabetes Mellitus

GRB10 rs1800504 Polymorphism Is Associated With the Risk of Coronary Heart Disease in Patients With Type 2 Diabetes Mellitus

mTOR: A Potential New Target in Nonalcoholic Fatty Liver Disease

TGF-β1 promotes SCD1 expression via the PI3K-Akt-mTOR-SREBP1 signaling pathway in lung fibroblasts

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