Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice

Tripathy, Sasmita; Jump, Donald Β.

doi:10.1194/jlr.m028787

Cited by 53 publications

(52 citation statements)

References 55 publications

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“…In order to study the mechanisms responsible for hepatic lipid alterations, we employed HepG2 cells, which are able to develop cellular steatosis and are frequently used for respective mechanistic studies ( 15,(41)(42)(43)(44). The fatty acid chain length, in fact, depended on the presence of p62; when p62 was knocked down in HepG2 cells, increased levels of C16 fatty acids were detectable ( Table 2 ), so that the ratio of C18 to C16 fatty acids decreased ( Fig.…”

Section: Characterization Of Steatosismentioning

confidence: 99%

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

Laggai

Kessler

Boettcher

et al. 2014

Journal of Lipid Research

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Nonalcoholic fatty liver disease (NAFLD) is considered to be the most common liver disorder in Western countries with a prevalence of 20-30% of the adult population ( 1, 2 ). There is a strong correlation between the characteristics of the metabolic syndrome, such as obesity and diabetes mellitus, and NAFLD/nonalcoholic steatohepatitis (NASH) ( 3 ).The "two-hit" hypothesis represents a common model to describe the development and progression of fatty liver diseases. A simple steatosis can stand for the fi rst step in early liver pathogenesis ( 4, 5 ). The progression from simple steatosis to NASH requires a "second hit" mediated by reactive oxygen species and release of infl ammatory cytokines ( 6 ). This infl ammatory environment can result in hepatic cirrhosis and fi nally in hepatocellular carcinoma (HCC) ( 7 ).The development of hepatosteatosis can be induced by different mechanisms. The synthesis of lipids is regulated in a complex interplay induced by a set of lipogenic transcription factors, among which liver X receptor ␣ (LXR-␣ / NR1H3), sterol regulatory element binding transcription factor 1 (SREBF1/SREBP1), and carbohydrate responsive element binding protein (ChREBP/MLXIPL) represent the most important ones ( 8 ). In this context, the fact that MLXIPL controls 50% of hepatic lipogenesis by regulating glycolytic and lipogenic gene expression ( 9 ) illustrates the Abstract Liver-specifi c overexpression of the insulin-like growth factor 2 ( IGF2 ) mRNA binding protein p62/ IGF2BP2-2 induces a fatty liver, which highly expresses IGF2 . Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These fi ndings underline the detrimental role of p62 in liver disease. -Laggai, S., S. M. Kessler, S.

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Section: Characterization Of Steatosismentioning

confidence: 99%

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

Laggai

Kessler

Boettcher

et al. 2014

Journal of Lipid Research

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“…*, p Ͻ 0.05. NOVEMBER 11, 2016 • VOLUME 291 • NUMBER 46 cenic acid from palmitoleic acid in hepatocytes (32,33), so it is possible that this enzyme is significantly reduced in Plin2-null animals on CD. We observed striking decreases in Elovl5 gene expression for knock-out animals on WD.…”

Section: Loss Of Plin2 Results In Altered Hepatic Neutral Lipid Profimentioning

confidence: 99%

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

Libby¹,

Bales²,

Orlicky

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanPerilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease. Mice with or without whole-body deletion of perilipin-2 (Plin2-null) were fed either Western or control diets for 30 weeks. Perilipin-2 deletion prevents obesity and insulin resistance in Western diet-fed mice and dramatically reduces hepatic triglyceride and cholesterol levels in mice fed Western or control diets. Gene and protein expression studies reveal that PLIN2 deletion suppressed SREBP-1 and SREBP-2 target genes involved in de novo lipogenesis and cholesterol biosynthetic pathways in livers of mice on either diet. GC-MS lipidomics demonstrate that this reduction correlated with profound alterations in the hepatic lipidome with significant reductions in both desaturation and elongation of hepatic neutral lipid species. To examine the possibility that lipidomic actions of PLIN2 deletion contribute to suppression of SREBP activation, we isolated endoplasmic reticulum membrane fractions from long-term Western diet-fed wild type (WT) and Plin2-null mice. Lipidomic analyses reveal that endoplasmic reticulum membranes from Plin2-null mice are markedly enriched in -3 and -6 long-chain polyunsaturated fatty acids, which others have shown inhibit SREBP activation and de novo lipogenesis. Our results identify PLIN2 as a determinant of global changes in the hepatic lipidome and suggest the hypothesis that these actions contribute to SREBP-regulated de novo lipogenesis involved in non-alcoholic fatty liver disease.

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“…While the mechanism for Elovl5 control of blood glucose and GNG was linked to cis -VA synthesis and its regulation of the mammalian target of rapamycin complex 2-thymoma viral proto-oncogeneforkhead box O1 (mTORC2-AKT-FoxO1) pathway ( 14,19 ), the mechanism for Elovl5 control of HTG is unknown.…”

Section: Measurement Of Plasma ␤ -Hydroxybutyrate and Htgmentioning

confidence: 99%

“…Total RNA was extracted from mouse liver, AML12, and HepG2 cells using TRIzol (Invitrogen), and transcript levels were measured by quantitative RT-PCR (qRT-PCR) as described ( 14,19 ). Gene-specifi c primers are listed in (supplementary Table I).…”

Section: Rna Extraction and Quantitative Real-time Pcrmentioning

confidence: 99%

Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice

Tripathy

Lytle

Stevens

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org populations. NAFLD is the hepatic manifestation of metabolic syndrome and is associated with a cluster of metabolic risk factors including obesity, dyslipidemia, type 2 diabetes, and hypertension ( 1 ). The prevalence of NAFLD is ‫ف‬ 30% in US adults but is as high as 90-95% in obese individuals and у 60% in type 2 diabetic subjects ( 2 ). NAFLD is viewed as a pathological spectrum with benign fatty liver at one end and nonalcoholic steatohepatitis (NASH; infl ammation, oxidative stress, hepatic damage, and fi brosis) at the other end ( 1 ). Thirty to 40% of individuals with simple fatty liver develop NASH, which can progress to cirrhosis, a risk factor for hepatic cancer ( 3 ).NAFLD involves excessive neutral lipid storage in the liver as TG, cholesteryl ester, and diacylglycerol (DAG) ( 4-6 ). NEFAs used for TG synthesis are derived from multiple sources including those mobilized from adipose tissue, Abstract Nonalcoholic fatty liver disease is a major public health concern in the obese and type 2 diabetic populations. Nonalcoholic fatty liver disease (NAFLD) is a signifi cant public health concern for the obese and type 2 diabetic

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Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice

Cited by 53 publications

References 55 publications

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice

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