SREBP-1c overexpression induces triglycerides accumulation through increasing lipid synthesis and decreasing lipid oxidation and VLDL assembly in bovine hepatocytes

Li, Xinwei; Yu, Longquan; Yang, Wentao; Xiao, Chong; Fu, Shixin; Deng, Qinghua; Ding, Hongyan; Wang, Zhe

doi:10.1016/j.jsbmb.2014.02.009

Cited by 77 publications

(55 citation statements)

References 45 publications

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“…[28][29][30][31] SREBP-1 is also associated with cell growth and has been reported to promote cell growth and survival. 32,33 SREBP-1 silencing has been reported to cause a reduction in cell viability, organ size, and cell proliferation, but the molecular mechanisms have not yet been elucidated. 13,28,34 Previous reports also established that SREBP-1c acts downstream of mTOR.…”

Section: Discussionmentioning

confidence: 99%

U2AF65 enhances milk synthesis and growth of bovine mammary epithelial cells by positively regulating the mTOR‐SREBP‐1c signalling pathway

Zhen

et al. 2019

Cell Biochemistry & Function

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U2 snRNP auxiliary factor 65 kDa (U2AF65) is a splicing factor that promotes prespliceosome assembly. The function of U2AF65 in alternative splicing has been identified; however, the essential physiological role of U2AF65 remains poorly understood. In this study, we investigated the regulatory role of U2AF65 in milk synthesis and growth of bovine mammary epithelial cells (BMECs). Our results showed that U2AF65 localizes in the nucleus. Treatment with amino acids (Met and Leu) and hormones (prolactin and β-estradiol) upregulated the expression of U2AF65 in these cells. U2AF65 overexpression increased the synthesis of β-casein, triglycerides, and lactose; increased cell viability; and promoted proliferation of BMECs. Furthermore, our results showed that U2AF65 positively regulated mTOR phosphorylation and expression of mature mRNA of mTOR and SREBP-1c. Collectively, our findings demonstrate that U2AF65 regulates the mRNA expression of signalling molecules (mTOR and SREBP-1c) involved in milk synthesis and growth of BMECs, possibly via controlling the splicing and maturation of these mRNAs. U2 snRNP auxiliary factor 65 kDa (U2AF65) is a splicing factor that promotes prespliceosome assembly. The essential physiological role of U2AF65 remains poorly understood. In the present study, we confirmed that U2AF65 functions as a positive regulator of milk synthesis in and proliferation of bovine mammary epithelial cells via the mTOR-SREBP-1c signalling pathway. Therefore, our study uncovers the regulatory role of U2AF65 in milk synthesis and cell proliferation. KEYWORDS U2AF65, mTOR, SREBP-1c, β-casein, triglyceride, lactose 1 | INTRODUCTION U2 small nuclear ribonucleoprotein (U2snRNP) auxiliary factor (U2AF) is a conserved nuclear factor that plays a crucial role in mRNA splicing. U2AF is a stable heterodimer comprising U2AF65 subunit (65 kDa), which is encoded by U2AF2 gene, and the U2AF35 (35 kDa) subunit, which is encoded by the U2AF1 gene. U2AF65 interacts with the polypyrimidine tract (PPT), a conserved 3′ splice-site (ss) immediately downstream of the branch point sequence (BPS). On the other hand, U2AF35 interacts with invariant AG dinucleotides at the 3′ ss and stabilizes the binding of U2AF65 with RNA. 1,2A series of U2AF mutations have been characterized to investigate the functions of U2AF as a splicing factor, and previous studies have revealed that the stoichiometry of U2AF is important for accurate 3′ ss selection. 3,4 Consistent with the disease phenotype of myelodysplasia, one study indicated that mutations in U2AF cause widespread changes in alternative splicing and is linked to decreased cell proliferation. 5 U2AF has also been reported to be involved in other cellular processes, such as mRNA export, in which it binds to

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Section: Discussionmentioning

confidence: 99%

U2AF65 enhances milk synthesis and growth of bovine mammary epithelial cells by positively regulating the mTOR‐SREBP‐1c signalling pathway

Zhen

et al. 2019

Cell Biochemistry & Function

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“…SREBP-1c is one member of this family that may regulate many genes involved in lipid synthesis and deposition25, such as ACC1, SCD-1, and FAS, which are required for fatty acid synthesis in white adipose tissue, the liver, skeletal muscle, and other tissues26. The incidence of fatty liver increased when the expression levels of SREBP-1c and its target genes, FAS and ACC1, were enhanced significantly in bovine hepatocytes27. PPARs are involved in the transport of TG in the blood, cellular fatty acid uptake, and mitochondrial beta oxidation28.…”

Section: Discussionmentioning

confidence: 99%

A High-Concentrate Diet Induced Milk Fat Decline via Glucagon-Mediated Activation of AMP-Activated Protein Kinase in Dairy Cows

Cao

Xie

et al. 2017

Sci Rep

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Dairy cows are often fed a high-concentrate (HC) diet to meet lactation demands; however, long-term concentrate feeding is unhealthy and decreases milk fat. Therefore, we investigated the effects of liver lipid metabolism on milk fat synthesis. Ten lactating Holstein cows were assigned randomly into HC and LC (low-concentrate) diet groups. After 20 weeks of feeding, milk fat declined, and lipopolysaccharide levels in the jugular, portal, and hepatic veins increased in the HC group. Liver consumption and release of nonesterified fatty acid (NEFA) into the bloodstream also decreased. AMP-activated protein kinase alpha (AMPKα) was up-regulated significantly in the livers of the HC-fed cows. The HC diet also up-regulated the expression of the transcription factor peroxisome proliferator-activated receptor α (PPARα) and its downstream targets involved in fatty acid oxidation, including carnitine palmitoyltransferase-1,2 (CPT-1, CPT-2), liver-fatty acid-binding protein (L-FABP), and acyl-CoA oxidase (ACO). The HC diet increased blood glucagon (GC) levels, and liver glucagon receptor (GCGR) expression was elevated. Cumulatively, a long-term HC diet decreased plasma concentrations of NEFA via the GC/GCGR-AMPK-PPARα signalling pathway and reduced their synthesis in the liver. The decreased NEFA concentration in the blood during HC feeding may explain the decline in the milk fat of lactating cows.

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“…SREBPs are a family of transcription factors that regulate lipid homeostasis by controlling the expression of a range of enzymes required for endogenous cholesterol, fatty acid, triacylglycerol, and phospholipid synthesis [26,27]. The active form of SREBP, the 68-kDa fragment (NH2-SREBP-1, nSREBP-1), can translocate into the nuclei and regulate target gene transcription through binding to sterol-regulatory elements in the specific promoter regions [28].…”

Section: Discussionmentioning

confidence: 99%

Ezetimibe-Mediated Protection of Vascular Smooth Muscle Cells from Cholesterol Accumulation through the Regulation of Lipid Metabolism-Related Gene Expression

Gong

Sun²,

Yuan³

et al. 2014

Pharmacology

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Background: Ezetimibe is a potent inhibitor of Niemann-Pick type C1-Like 1 and has been approved for the treatment of hypercholesterolemia. Our preliminary study showed that ezetimibe promotes cholesterol efflux from vascular smooth muscle cells (VSMCs). Our aim was to investigate the cellular mechanisms underlying the ezetimibe actions. Methods and Results: Rat VSMCs were converted to foam cells by incubation with cholesterol:methyl-F-cyclodextrin. The intracellular free cholesterol, total cholesterol, and the ratio of cholesteryl ester to total cholesterol were decreased after the incubation of VSMCs with different concentrations of ezetimibe (3, 10, 30, and 30 Vmol/l) or treated with 30 Vmol/l of ezetimibe for different time periods (6, 12, 24, and 48 h). Our results also showed that the expression of caveolin-1, liver X receptor E, and ATP-binding cassette transporter ABCA1 was enhanced, but the expression of nSREBP-1c was decreased in a concentration- and time-dependent manner. RNA interference was used to determine the roles of caveolin-1 and SREBP-1 in the lipid-lowering effect of ezetimibe. The results showed that caveolin-1 was involved in the regulation of intracellular cholesterol content, and the expression of caveolin-1 was repressed by SREBP-1. Conclusion: The present study indicates that ezetimibe protects VSMCs from cholesterol accumulation by regulating the expression of lipid metabolism-related genes. i 2014 S. Karger AG, Basel

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SREBP-1c overexpression induces triglycerides accumulation through increasing lipid synthesis and decreasing lipid oxidation and VLDL assembly in bovine hepatocytes

Cited by 77 publications

References 45 publications

U2AF65 enhances milk synthesis and growth of bovine mammary epithelial cells by positively regulating the mTOR‐SREBP‐1c signalling pathway

U2AF65 enhances milk synthesis and growth of bovine mammary epithelial cells by positively regulating the mTOR‐SREBP‐1c signalling pathway

A High-Concentrate Diet Induced Milk Fat Decline via Glucagon-Mediated Activation of AMP-Activated Protein Kinase in Dairy Cows

Ezetimibe-Mediated Protection of Vascular Smooth Muscle Cells from Cholesterol Accumulation through the Regulation of Lipid Metabolism-Related Gene Expression

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