ER phospholipid composition modulates lipogenesis during feeding and in obesity

Rong, Xianglu; Wang, Bo; Palladino, Elisa N.D.; Vallim, Thomas Q. de Aguiar; Ford, David A.; Tontonoz, Peter

doi:10.1172/jci93616

Cited by 80 publications

(86 citation statements)

References 37 publications

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“…It is possible that this effect is mediated by elaidate‐induced changes in ER membrane composition, for instance involving an altered ratio of phospholipids to cholesterol or changes in fatty acid composition. Consistent with this line of reasoning, it was recently shown that increased incorporation of poly‐unsaturated fatty acids into phospholipids in the ER accelerated SREBP1c processing through a mechanism that required an intact SCAP pathway . Overall, our data suggest that elaidate activates SREBP2 signaling through complementary mechanisms that include lowering intracellular free cholesterol levels and desensitizing SCAP to cholesterol, possibly involving changes in ER membrane composition.…”

Section: Discussionsupporting

confidence: 89%

Industrial Trans Fatty Acids Stimulate SREBP2‐Mediated Cholesterogenesis and Promote Non‐Alcoholic Fatty Liver Disease

Oteng

Loregger

Weeghel

et al. 2019

Molecular Nutrition Food Res

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Scope The mechanisms underlying the deleterious effects of trans fatty acids on plasma cholesterol and non‐alcoholic fatty liver disease (NAFLD) are unclear. Here, the aim is to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods and 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 shows that elaidate but not oleate or palmitate induces expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate is mediated by increased sterol regulatory element‐binding protein 2 (SREBP2) activity and is dependent on SREBP cleavage–activating protein (SCAP), yet independent of liver‐X receptor and ubiquitin regulatory X domain‐containing protein 8. Elaidate decreases intracellular free cholesterol levels and represses the anticholesterogenic effect of exogenous cholesterol. In mice, the trans‐unsaturated diet increases the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, alanine aminotransferase activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis‐unsaturated and saturated diets. Conclusion Elaidate induces cholesterogenesis in vitro by activating the SCAP–SREBP2 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.

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Section: Discussionsupporting

confidence: 89%

Industrial Trans Fatty Acids Stimulate SREBP2‐Mediated Cholesterogenesis and Promote Non‐Alcoholic Fatty Liver Disease

Oteng

Loregger

Weeghel

et al. 2019

Molecular Nutrition Food Res

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“…On an HSD diet, hepatic Elovl6 deficiency markedly reduced the nuclear levels of SREBP‐1, indicating that hepatic Elovl6 expression and its products are required for the maturation and nuclear translocation of active SREBP‐1 protein. Although the mechanism whereby Elovl6 deficiency reduces the maturation of SREBP‐1 protein and Srebf1c mRNA expression remains to be elucidated, a recent study has suggested that the altered acyl‐chain composition of PLs in the ER induced by Elovl6 deficiency may reduce SREBP‐1 posttranslational processing …”

Section: Discussionmentioning

confidence: 99%

Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl‐Chain Length and Hepatic Insulin Sensitivity in Mice

et al. 2020

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BaCKgRoUND aND aIMS:Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity-induced insulin resistance by modifying hepatic C16/C18-related FA composition. appRoaCH aND ReSUltS: To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liverspecific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high-fat diet-induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high-sucrose diet (HSD), which induces lipogenesis. Hepatic patatinlike phospholipase domain-containing protein 3 (Pnpla3) expression was down-regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD-fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1/18:0) content was lower in

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“…12 compared the addition of LysoPC 18:1 to that of LysoPC 18:0. LysoPC 16:0 is a preferred substrate for lysophosphatidylcholine acyltransferase 3 (Lpcat3) (17)(18)(19). Therefore, we compared adding LysoPC 18:1, LysoPC 18:0, or LysoPC 16:0 to chow.…”

Section: Lysopc 16:0 Acts Like Lysopc 18:0 and Not Like Lysopc 18:1mentioning

confidence: 99%

Role of enterocyte stearoyl-Co-A desaturase-1 in LDLR-null mice

Mukherjee

Hough

Chattopadhyay

et al. 2018

Journal of Lipid Research

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After crossing floxed stearoyl-CoA desaturase-1 ( ) mice with LDL receptor-null ( ) mice, and then Villin Cre () mice, enterocyte expression in / / mice was reduced 70%. On Western diet (WD), / mice gained more weight than / / mice ( < 0.0023). On WD, jejunum levels of lysophosphatidylcholine (LysoPC) 18:1 and lysophosphatidic acid (LPA) 18:1 were significantly less in / / compared with / mice ( < 0.0004 and < 0.026, respectively). On WD, / / mice compared with / mice had lower protein levels of lipopolysaccharide-binding protein (LBP), cluster of differentiation 14 (CD14), toll-like receptor 4 (TLR4), and myeloid differentiation factor-88 (MyD88) in enterocytes and plasma, and less dyslipidemia and systemic inflammation. Adding a concentrate of tomatoes transgenic for the apoA-I mimetic peptide 6F (Tg6F) to WD resulted in reduced enterocyte protein levels of LBP, CD14, TLR4, and MyD88 in / mice similar to that seen in / / mice. Adding LysoPC 18:1 to WD did not reverse the effects of enterocyte knockdown. Adding LysoPC 18:1 (but not LysoPC 18:0) to chow induced jejunum expression and increased dyslipidemia and plasma serum amyloid A and interleukin 6 levels in / mice, but not in / / mice. We conclude that enterocyte is partially responsible for LysoPC 18:1- and WD-induced dyslipidemia and inflammation in mice.

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ER phospholipid composition modulates lipogenesis during feeding and in obesity

Cited by 80 publications

References 37 publications

Industrial Trans Fatty Acids Stimulate SREBP2‐Mediated Cholesterogenesis and Promote Non‐Alcoholic Fatty Liver Disease

Industrial Trans Fatty Acids Stimulate SREBP2‐Mediated Cholesterogenesis and Promote Non‐Alcoholic Fatty Liver Disease

Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl‐Chain Length and Hepatic Insulin Sensitivity in Mice

Role of enterocyte stearoyl-Co-A desaturase-1 in LDLR-null mice

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