Ablation of the very‐long‐chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet‐induced obesity

Zadravec, Damir; Brolinson, Annelie; Fisher, Rachel M.; Carneheim, C.; Csikasz, Robert I.; Bertrand‐Michel, Justine; Borén, Jan; Guillou, Hervé; Rudling, Mats; Jacobsson, Anders

doi:10.1096/fj.09-152298

Cited by 97 publications

(76 citation statements)

References 45 publications

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“…Moreover, C18:1 and C20:1 VLCFAs could bind PPAR␥ in vitro (Fig. 6), whose data supported that C18:1 VLCFA acts as PPAR␥ ligand (21,23,25,45) with increasing triglyceride and enhancement of the expression of adipogenic genes such as PPAR␥ and lipoprotein lipase (25). Our data presented here support the notion that VLCFAs are powerful molecules and suggest that, by manipulating the synthesis of saturated and monounsaturated C18 -24 VLCFAs, it may be possible to influence adipose tissue expansion.…”

Section: Discussionsupporting

confidence: 60%

Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells

Kobayashi

Fujimori

2012

American Journal of Physiology-Endocrinology and Metabolism

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Section: Discussionsupporting

confidence: 60%

Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells

Kobayashi

Fujimori

2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Fatty acid assay was performed as described in ( 33 ). Following homogenization of liver samples in methanol/5 mM EGTA (2:1, v/v), lipids corresponding to an equivalent of 1 mg of liver were extracted in the presence of glyceryl triheptadecanoate (0.5 g) as an internal standard.…”

Section: Gc Analysismentioning

confidence: 99%

In vivo hepatic lipid quantification using MRS at 7 Tesla in a mouse model of glycogen storage disease type 1a

Ramamonjisoa

Ratiney

Mutel

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org Glycogen storage disease type 1 (GSD 1) is an autosomal recessive metabolic disorder resulting in severe impairment of glucose production and large accumulation of lipids within hepatocytes (steatosis) ( 1, 2 ). The phenotype of GSD 1 results from a defect in the glucose-6 phosphatase (G6Pase) complex, leading to severe hypoglycemia due to the loss of endogenous glucose production. Despite a strict diet, patients with GSD 1 develop hepatomegaly and steatosis and may develop, with age, hepatocellular adenoma that can ultimately evolve into hepatocellular carcinoma ( 3, 4 ). Recently, a viable mouse model of GSD 1a with a liverspecifi c deletion of G6Pase catalytic subunit (L-G6pc Ϫ / Ϫ ) has been generated and validated ( 5 ). GSD 1a mice exhibit hepatic pathological features very similar to those observed in GSD 1a patients.The accumulation of lipids in the liver relates to the buildup of neutral lipids, such as triglycerides (TGs) and cholesterol esters, stored as lipid droplets in hepatocytes and leading to hepatic steatosis. This fat accumulation may originate from a ) peripheral fat stored in adipose tissue that fl ows to the liver as plasma nonesterifi ed fatty acids, b ) fatty acids newly made within the liver through de novo lipogenesis, and c ) dietary fatty acids ( 6, 7 ).Steatosis is highly linked to the development of metabolic diseases such as obesity or type 2 diabetes, but it can also result from genetic disorders impacting lipid and glucose metabolism such as in GSD 1a, ␣ 1-antitrypsin defi ciency, Abstract The assessment of liver lipid content and composition is needed in preclinical research to investigate steatosis and steatosis-related disorders. The purpose of this study was to quantify in vivo hepatic fatty acid content and composition using a method based on short echo time proton magnetic resonance spectroscopy (MRS) at 7 Tesla. A mouse model of glycogen storage disease type 1a with inducible liver-specifi c deletion of the glucose-6-phosphatase gene (L-G6pc ؊ / ؊ ) mice and control mice were fed a standard diet or a high-fat/high-sucrose (HF/HS) diet for 9 months. In control mice, hepatic lipid content was found signifi cantly higher with the HF/HS diet than with the standard diet. As expected, hepatic lipid content was already elevated in L-G6pc ؊ / ؊ mice fed a standard diet compared with control mice. L-G6pc ؊ / ؊ mice rapidly developed steatosis which was not modifi ed by the HF/HS diet. On the standard diet, estimated amplitudes from olefi nic protons were found signifi cantly higher in L-G6pc ؊ / ؊ mice compared with that in control mice. L-G6pc ؊ / ؊ mice showed no noticeable polyunsaturation from diallylic protons. Total unsaturated fatty acid indexes measured by gas chromatography were in agreement with MRS measurements. These results showed the great potential of high magnetic fi eld MRS to follow the diet impact and lipid alterations in mouse liver.

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“…3C), which may trigger excess lipid storage in WAT. ELOVL3 knockout females are resistant to DIO, probably due to a lack of very-long-chain fatty acids (VLCFAs) that stimulate expansion of lipid droplets (34). In Rsl1 Ϫ/Ϫ females, upregulated ELOVL3 in liver during HFD may increase synthesis of VLCFAs that could act in liver or be transported (possibly via lipocalins) to act in WAT to sustain lipogenesis and lead to weight gain (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…3C). Furthermore, Elovl3 is likely to play a key role in the phenotype of Rsl1 Ϫ/Ϫ mice given that Elovl3 knockout females are resistant to DIO (34). Major urinary protein 1 (Mup1) was also markedly upregulated in Rsl1 Ϫ/Ϫ female livers for mice on HFD (Fig.…”

Section: Rsl1mentioning

confidence: 95%

The KRAB Zinc Finger Protein RSL1 Modulates Sex-Biased Gene Expression in Liver and Adipose Tissue To Maintain Metabolic Homeostasis

Krebs

Zhang

Yin

et al. 2014

Molecular and Cellular Biology

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b Krüppel-associated box zinc finger proteins (KRAB-ZFPs) are a huge family of vertebrate-specific repressors that modify gene expression in an epigenetic manner. Despite a well-defined repression mechanism, few biological roles or gene targets of KRAB-ZFP are known. Regulator of sex-limitation 1 (RSL1) is a mouse KRAB-ZFP that enforces male-predominant expression in the liver, affecting body mass and pubertal timing. Here we show that female but not male Rsl1 ؊/؊ mice gain more weight than wildtype mice on a high-fat diet (HFD) and that key liver and white adipose tissue (WAT) metabolic genes are altered in both Rsl1 ؊/؊ sexes in response to dietary stress. Expression profiling of Rsl1-sensitive genes in liver and WAT indicates that RSL1 accentuates sex-biased gene expression in liver but greatly diminishes it in WAT. RSL1 expression solely in liver is sufficient to limit dietinduced weight gain and suppress lipogenic genes in WAT, indicating that RSL1 balances metabolism via liver-to-adipose-tissue communication. RSL1's effects on adult physiology exemplify a significant modulatory capacity of KRAB-ZFPs, in the absence of which there is widespread metabolic dysregulation. This ability to buffer against gene expression noise, coupled with extensive individual genetic variation, highlights the enormous potential of KRAB-Zfp genes as candidate risk factors for complex diseases.

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Ablation of the very‐long‐chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet‐induced obesity

Cited by 97 publications

References 45 publications

Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells

Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells

In vivo hepatic lipid quantification using MRS at 7 Tesla in a mouse model of glycogen storage disease type 1a

The KRAB Zinc Finger Protein RSL1 Modulates Sex-Biased Gene Expression in Liver and Adipose Tissue To Maintain Metabolic Homeostasis

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