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Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [3T3-L1]

ABSTRACT: Scope: Consumption of industrial trans fatty acids unfavourably alters plasma cholesterol and has been linked to NAFLD. However, the mechanisms underlying these deleterious effects of trans fatty acids are unclear. Here, we aim to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods & Results: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells showed that elaidate but not oleate or palmitate induced expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate was mediated by increased SREBP2 and dependent on SCAP, yet independent of LXR and UBXD8. Elaidate decreased intracellular free cholesterol levels and repressed the anti-cholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increased the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, ALT activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. Conclusion: Elaidate induces cholesterogenesis in vitro via activation of the SCAP-SREBP axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.

ORGANISM(S): Mus musculus

PROVIDER: GSE136351 | GEO | 2019/08/27

REPOSITORIES: GEO

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Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [Hepa1-6 cells]

Project description:Scope: Consumption of industrial trans fatty acids unfavourably alters plasma cholesterol and has been linked to NAFLD. However, the mechanisms underlying these deleterious effects of trans fatty acids are unclear. Here, we aim to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods & Results: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells showed that elaidate but not oleate or palmitate induced expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate was mediated by increased SREBP2 and dependent on SCAP, yet independent of LXR and UBXD8. Elaidate decreased intracellular free cholesterol levels and repressed the anti-cholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increased the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, ALT activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. Conclusion: Elaidate induces cholesterogenesis in vitro via activation of the SCAP-SREBP axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.

2019-08-27 | GSE136278 | GEO

Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [liver]

2019-08-27 | GSE136271 | GEO

Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [Hepa1-6 cells]

Project description:Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [Hepa1-6 cells]

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Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease

Project description:Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease

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Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [liver]

Project description:Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [liver]

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Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [3T3-L1]

Project description:Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [3T3-L1]

| PRJNA562280 | ENA

ARMC5 selectively degrades SCAP-free SREBF1 and is essential for fatty acid desaturation in adipocytes

Project description:Background: Armadillo repeat containing 5 (ARMC5)-CUL3 complex was recently identified as an E3 ubiquitin ligase of full-length SREBF. Although ARMC5 was involved in SREBF2 pathway in the adrenocortical cells and might participate in the development of primary bilateral macronodular adrenal hyperplasia (PBMAH), the role of ARMC5 in adipocytes has not been investigated. Methods and Results: Adipocyte-specific Armc5 knockout mice were generated. In the white adipose tissue (WAT) of these mice, all the stearoyl-CoA desaturase (Scd) were drastically downregulated under refed condition and high fat-high sucrose diet. Consistently, unsaturated fatty acids were decreased, while saturated fatty acids were increased in the WAT of these mice. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) peaks at the SREBF1-binding sites were markedly diminished around the Scd1 locus in the WAT of adipocyte-specific Armc5 knockout mice. Armc5-deficient 3T3-L1 adipocytes also exhibited downregulation of Scd. Mechanistically, disruption of Armc5 restored decreased full-length SREBF1 in the CHO cells deficient for Scap, an escort protein required for the transport of SREBF from the ER to the Golgi. In HEK293T cells, overexpression of Scap inhibited ARMC5-mediated degradation of full-length SREBF1, and overexpression of Armc5 increased nuclear SREBF1/full-length SREBF1 ratio in the presence of exogenous Scap in HEK293T cells. Conclusions: ARMC5 exerts selective removal of SCAP-free SREBF1 and stimulates SCAP-mediated SREBF1 processing, hence is essential for fatty acid desaturation in vivo.

2024-12-19 | GSE262941 | GEO

RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [m6A-seq]

Project description:Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor of hepatocellular carcinoma (HCC). However, the mechanism and target therapy on NAFLD-HCC are still unclear. Here, we identify that the N6-methyladenosine (m6A) methyltransferase METTL3 promotes NAFLD-HCC. Hepatocyte-specific Mettl3 knockin exacerbated NAFLD-HCC formation while Mettl3 knockout exerted an opposite effect in mice. Single-cell RNA-seq revealed that METTL3 suppressed antitumor immune response by reducing infiltration of Gzmb+ and IFN-γ+ CD8+ T-cell, thereby facilitating immune escape. Mechanistically, METTL3 mediates SCAP mRNA m6A to promote its translation, leading to the activation of cholesterol biosynthesis. This enhanced secretion of cholesterol and cholesteryl esters, lipotoxins that impaired CD8+ T cell function in tumor microenvironment. Targeting of METTL3 by sgRNA, nanoparticle-siRNA, or pharmacological inhibitor (STM2457) in combination with anti-PD1 synergized to reinvigorate cytotoxic CD8+ T cells and mediate tumor regression. Together, METTL3 is a therapeutic target in NAFLD-HCC, especially in conjunction with immune checkpoint blockade (ICB) therapy.

2023-08-23 | GSE233807 | GEO

RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [RNA-Seq]

2023-08-23 | GSE233806 | GEO

Pancreatic ductal adenocarcinoma tumor growth requires SREBP pathway activity

Project description:Tumor growth outstrips local nutrient supply, making metabolic reprogramming a necessary component of oncogenesis and cancer progression. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell division. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for cholesterol and fatty acid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including glioblastoma, breast, colon, liver and prostate. However, the role the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrate that SREBP target genes are upregulated in PDAC tumors, and SREBPs are upregulated in patient-derived PDAC cell lines under low serum conditions that mimic the tumor microenvironment. Chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Using subcutaneous and orthotopic xenograft models, we showed that SCAP is required for PDAC tumor growth. Pancreas-specific knockout of Scap had no effect on mouse pancreas development or function, allowing examination of the role for Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap significantly prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor inception. Collectively, these results demonstrate that SCAP and SREBP pathway activity are essential for PDAC cell and tumor growth in vitro and in vivo, identifying SCAP as a potential therapeutic target for PDAC.

2024-10-09 | GSE235100 | GEO

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