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

Matsuzaka, Takashi; Kuba, Motoko; Koyasu, Saori; Yamamoto, Yuta; Motomura, Kaori; Arulmozhiraja, Sundaram; Ohno, Hiroshi; Sharma, Rahul Kumar; Shimura, Takuya; Okajima, Yuka; Han, Song‐iee; Aita, Yuichi; Mizunoe, Yuhei; Osaki, Yoshinori; Iwasaki, Hitoshi; Yatoh, Shigeru; Suzuki, Hiroaki; Sone, Hirohito; Takeuchi, Yoshinori; Yahagi, Naoya; Miyamoto, Takafumi; Sekiya, Motohiro; Nakagawa, Yoshimi; Ema, Masatsugu; Takahashi, Satoru; Tokiwa, Hiroaki; Shimano, Hitoshi

doi:10.1002/hep.30953

Cited by 53 publications

(36 citation statements)

References 52 publications

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“…Thus, effects may be tissue specific. Recently, it has been shown that the lipid enzyme CerS4, that generates C18‐ and C20‐ceramides, contribute to hepatic insulin resistance 31 . Consistently, in HFD‐fed mice, we observed increases in hepatic C18‐, C20‐, and C22‐ceramides and the NA‐supplemented diet returned C20‐ and C22‐ceramides back to control levels.…”

Section: Discussionsupporting

confidence: 87%

Nervonic acid limits weight gain in a mouse model of diet‐induced obesity

et al. 2020

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Lipid perturbations contribute to detrimental outcomes in obesity. We previously demonstrated that nervonic acid, a C24:1 ω-9 fatty acid, predominantly acylated to sphingolipids, including ceramides, are selectively reduced in a mouse model of obesity. It is currently unknown if deficiency of nervonic acid-sphingolipid metabolites contribute to complications of obesity. Mice were fed a standard diet, a high fat diet, or these diets supplemented isocalorically with nervonic acid. The primary objective was to determine if dietary nervonic acid content alters the metabolic phenotype in mice fed a high fat diet. Furthermore, we investigated if nervonic acid alters markers of impaired fatty acid oxidation in the liver. We observed that a nervonic acidenriched isocaloric diet reduced weight gain and adiposity in mice fed a high fat diet. The nervonic acid enrichment led to increased C24:1-ceramides and improved several metabolic parameters including blood glucose levels, and insulin and glucose tolerance. Mechanistically, nervonic acid supplementation increased PPARα and PGC1α expression and improved the acylcarnitine profile in liver. These alterations indicate improved energy metabolism through increased β-oxidation of fatty acids. Taken together, increasing dietary nervonic acid improves metabolic parameters in mice fed a high fat diet. Strategies that prevent deficiency of, or restore, nervonic acid may represent an effective strategy to treat obesity and obesity-related complications.

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Section: Discussionsupporting

confidence: 87%

Nervonic acid limits weight gain in a mouse model of diet‐induced obesity

et al. 2020

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“…Previous studies in mammals have verified the crucial role of elovl6 in insulin resistance [3,19]. Mice with a global deficiency for elovl6 could protect against diet-induced insulin resistance [3], and elovl6 specific deletion in the liver of mice ameliorated insulin resistance by reducing hepatic ceramide and protein phosphatase 2A activity [20]. However, studies on the relationship between elovl6 and insulin in fish have not been reported to date.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization, Nutritional and Insulin Regulation of Elovl6 in Rainbow Trout (Oncorhynchus mykiss)

Pang

Zhao

et al. 2020

Biomolecules

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Elongation of very long-chain fatty acids protein 6 (Elovl6) is a crucial enzyme in the synthesis of endogenous fatty acids, which participates in the energy balance and metabolic diseases. The main objective of this study was to explore the molecular characterization of Elovl6 and the regulation of elovl6 expression in response to dietary fatty acids and insulin. In the present study, the ORF (open reading frame) of Elovl6 from rainbow trout was cloned and characterized, which showed a high identity (87%) with mammals and other teleost. The results of quantitative PCR showed that the transcriptional levels of elovl6 from rainbow trout that were fed diets containing soybean oil (enriched with 18:2n-6, linoleic acid (LA)) or linseed oil (enriched with 18:3n-3, α-linolenic acid (ALA)) were lower than those in the group that were fed diets containing fish oil (enriched with 20:5n-3, eicosapentaenoic acid (EPA) and 22:6n-3, docosahexaenoic acid (DHA)). Correspondingly, mRNA expression of elovl6 in hepatocytes treated with DHA was dramatically higher than that in LA and ALA groups. The transcriptional expression of elovl6 in hepatocytes treated with insulin was also significantly increased. Moreover, the dual luciferase assay showed the transcription factor CREB1 dramatically up-regulated the promoter activity of elovl6, while FOXO1 significantly down-regulated the elovl6 promoter activity in rainbow trout. The differences in transcriptional expression of crbe1 and foxo1 may contribute to the increase or decrease of elovl6 expression in rainbow trout in response to fatty acids or insulin. These findings revealed the molecular characterization of elovl6 and the regulation of elovl6 expression by CREB1 and FOXO1 in rainbow trout in response to dietary fatty acids or insulin.

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“…Néanmoins, plusieurs études récentes montrent une implication des céramides hépatiques dans l'apparition de la stéatose et de la résistance hépatique à l'insuline [33][34][35][36][37][38]. Selon le tissu étudié, des espèces différentes de céramides peuvent être impliquées.…”

Section: Mécanisme D'action Des Céramidesunclassified

Céramides, acteurs cruciaux dans le développement de l’insulino-résistance et du diabète de type 2

2020

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L’insulino-résistance, qui caractérise le diabète de type 2 et l’obésité, est due à une diminution de l’action de l’insuline sur ses tissus cibles (foie, tissu adipeux, muscles squelettiques). Il est maintenant bien documenté qu’au niveau de ces tissus, l’accumulation ectopique d’acides gras, et en particulier de métabolites dérivés de ces acides gras, comme les céramides, joue un rôle crucial dans l’altération du message insulinique. Cette revue décrit le rôle majeur joué par les céramides dans le développement de l’insulino-résistance des tissus périphériques.

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

Cited by 53 publications

References 52 publications

Nervonic acid limits weight gain in a mouse model of diet‐induced obesity

Nervonic acid limits weight gain in a mouse model of diet‐induced obesity

Molecular Characterization, Nutritional and Insulin Regulation of Elovl6 in Rainbow Trout (Oncorhynchus mykiss)

Céramides, acteurs cruciaux dans le développement de l’insulino-résistance et du diabète de type 2

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