Liver-specific knockdown of long-chain acyl-CoA synthetase 4 reveals its key role in VLDL-TG metabolism and phospholipid synthesis in mice fed a high-fat diet

Singh, Amar; Kan, Chin Fung Kelvin; Kraemer, Fredric B.; Sobel, Raymond A.; Li, Jingwen

doi:10.1152/ajpendo.00503.2018

Cited by 23 publications

(28 citation statements)

References 57 publications

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“…To generate a liver‐specific SR‐B1‐deficient mouse model, we employed previously established shRNA technology (Singh, Kan, Kraemer, Sobel, & Liu, 2019) to deplete hepatic SR‐B1 using adenovirus expressing a mouse Sr‐b1 shRNA (Ad‐shSR‐B1). Mice fed a NCD were injected with Ad‐shSR‐B1 or Ad‐shU6‐C control virus.…”

Section: Resultsmentioning

confidence: 99%

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

et al. 2020

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Obeticholic acid (OCA) activates the farnesoid X receptor (FXR) to lower circulating total cholesterol (TC) and high density lipoprotein‐cholesterol (HDL‐C) concentrations and to stimulate fecal cholesterol excretion in mice by increasing hepatic SR‐B1 expression. Here we show that hepatic SR‐B1 depletion by an adenovirus expressing Sr‐b1 shRNA (Ad‐shSR‐B1) attenuated these beneficial effects of OCA in mice on a chow diet. The mRNA levels of ABC cholesterol transporter genes (Abca1, Abcg1, Abcg5, and Abcg8) were unchanged in the liver of hepatic SR‐B1‐depleted mice regardless of OCA treatment; however, a modest increase in Abca1, Abcg5, and Abcg8 mRNA levels was observed in the ileum of vehicle‐treated control mice and Abca1 and Abcg8 mRNA levels were increased more by OCA administration. OCA treatment of Sr‐b1 knock out (KO) mice (Sr‐b1‐/‐) fed a normal chow diet (NCD) displayed a similar lack of transhepatic cholesterol movement, as well as a modest increase in the levels of ileum cholesterol transporter expression. However, OCA treatment of Sr‐b1 KO mice fed a cholesterol‐enriched diet reduced circulating cholesterol and increased fecal cholesterol output to comparable degrees to that of wild‐type (WT) mice, and these effects were accompanied by substantial elevations of mRNA levels of Abca1, Abcg1, Abcg5, and Abcg8 in the ileum of Sr‐b1 KO mice. Our studies suggest that FXR activation stimulates intestinal cholesterol excretion and reduces diet‐induced hyperlipidemia through increased expression of ileal cholesterol transporters when hepatic SR‐B1‐mediated cholesterol movement is absent.

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Section: Resultsmentioning

confidence: 99%

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

et al. 2020

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“…Hepatic ACSL4 is coregulated with the phospholipid (PL)-remodeling enzyme lysophosphatidylcholine (LPC) acyltransferase 3 to modulate the plasma triglyceride (TG) metabolism. Liver-specific knockdown of ACSL4 revealed a substantial decrease in circulating VLDL-TG levels and lipid peroxidation in mice fed a high-fat diet (Singh et al, 2019).…”

Section: Differential Expression Analysis Of Liver Transcriptomesmentioning

confidence: 95%

Changes of liver transcriptome profiles following oxidative stress in streptozotocin-induced diabetes in mice

Guo

Mao

Yan

et al. 2020

PeerJ

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Background Oxidative-stress (OS) was causal in the development of cell dysfunction and insulin resistance. Streptozotocin (STZ) was an alkylation agent that increased reactive oxygen species (ROS) levels. Here we aimed to explore the oxidative-stress and related RNAs in the liver of STZ-induced diabetic mice. Methods RNA-sequencing was performed using liver tissues from STZ induced diabetic mice and controls. Pathway and Gene Ontology (GO) analyses were utilized to annotate the target genes. The differentially expressed RNAs involved in the peroxisome pathway were validated by qRT-PCR. The glucose metabolite and OS markers were measured in the normal control (NC) and STZ-induced diabetic mellitus (DM) group. Results The levels of serum Fasting insulin, HbA1c, Malondialdehyde (MDA) and 8-iso-prostaglandin F2α (8-iso-PGF2α) were significant higher in DM groups than NC group, while SOD activity decreased significantly in DM groups. We found 416 lncRNAs and 910 mRNAs were differentially expressed in the STZ-induced diabetic mice compared to the control group. OS associated RNAs were differentially expressed in the liver of STZ-induced diabetic mice. Conclusion This study confirmed that the OS was increased in the STZ-induced DM mice as evidenced by the increase of lipid peroxidation product MDA and 8-iso-PGF2α, identified aberrantly expressed lncRNAs and mRNAs in STZ-induced diabetic mice.

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“…Previous reports have demonstrated that ACSL4 expression is elevated in the livers of NAFLD patients or animals [67,68]. Amar B. Singh et al compared high-fat diet (HFD)fed ACSL4 knockdown (KD) mice with HFD-fed normal wild-type mice and found that plasma VLDL-TG, glucose metabolism and liver phospholipid synthesis require ACSL4 expression in the liver [69]. Serum VLDL-TG in ACSL4 KD mice was significantly reduced, while liver and plasma cholesterol levels were not significantly different between the groups, indicating that ACSL4 may direct PUFAs into the hepatocyte TG synthesis pathway [69].…”

Section: Mamsmentioning

confidence: 99%

“…Amar B. Singh et al compared high-fat diet (HFD)fed ACSL4 knockdown (KD) mice with HFD-fed normal wild-type mice and found that plasma VLDL-TG, glucose metabolism and liver phospholipid synthesis require ACSL4 expression in the liver [69]. Serum VLDL-TG in ACSL4 KD mice was significantly reduced, while liver and plasma cholesterol levels were not significantly different between the groups, indicating that ACSL4 may direct PUFAs into the hepatocyte TG synthesis pathway [69]. Voltage-dependent anion channel (VDACs) in the outer mitochondrial membrane (OMM) are physically linked to the ER Ca2+ release channel inositol 1,4,5-triphosphate receptor (IP3R) by GRP75 (a portion of which appears to be in the cytosol at the MAMs) and serve as channels for signalling molecules, including Ca2+, apoptotic signals, and metabolites.…”

Section: Mamsmentioning

confidence: 99%

Mutual interaction between endoplasmic reticulum and mitochondria in nonalcoholic fatty liver disease

Wang¹,

He²,

Tsai

et al. 2020

Lipids Health Dis

102

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Nonalcoholic fatty liver disease (NAFLD) is a common metabolic syndrome. Imbalances between liver lipid output and input are the direct causes of NAFLD, and hepatic steatosis is the pathological premise and basis for NAFLD progression. Mutual interaction between endoplasmic reticulum stress (ERS) and oxidative stress play important roles in NAFLD pathogenesis. Notably, mitochondria-associated membranes (MAMs) act as a structural bridges for functional clustering of molecules, particularly for Ca 2+ , lipids, and reactive oxygen species (ROS) exchange. Previous studies have examined the crucial roles of ERS and ROS in NAFLD and have shown that MAM structural and functional integrity determines normal ER-mitochondria communication. Upon disruption of MAM integrity, miscommunication directly or indirectly causes imbalances in Ca2+ homeostasis and increases ERS and oxidative stress. Here, we emphasize the involvement of MAMs in glucose and lipid metabolism, chronic inflammation and insulin resistance in NAFLD and summarize MAM-targeting drugs and compounds, most of which achieve their therapeutic or ameliorative effects on NAFLD by improving MAM integrity. Therefore, targeting MAMs may be a viable strategy for NAFLD treatment. This review provides new ideas and key points for basic NAFLD research and drug development centred on mitochondria and the endoplasmic reticulum.

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Liver-specific knockdown of long-chain acyl-CoA synthetase 4 reveals its key role in VLDL-TG metabolism and phospholipid synthesis in mice fed a high-fat diet

Cited by 23 publications

References 57 publications

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

FXR activation promotes intestinal cholesterol excretion and attenuates hyperlipidemia in SR‐B1‐deficient mice fed a high‐fat and high‐cholesterol diet

Changes of liver transcriptome profiles following oxidative stress in streptozotocin-induced diabetes in mice

Mutual interaction between endoplasmic reticulum and mitochondria in nonalcoholic fatty liver disease

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