Elovl6 promotes nonalcoholic steatohepatitis

Matsuzaka, Takashi; Atsumi, Ayaka; Matsumori, Rie; Tang, Nujiang; Shinozaki, Haruna; Suzuki-Kemuriyama, Noriko; Kuba, Motoko; Nakagawa, Yoshimi; Ishii, Kiyo‐aki; Shimada, Masako; Kobayashi, Kazuto; Yatoh, Shigeru; Takahashi, Akimitsu; Takekoshi, Kazuhiro; Sone, Hirohito; Yahagi, Naoya; Suzuki, Hiroaki; Murata, Soichiro; Nakamuta, Makoto; Yamada, Nobuhiro; Shimano, Hitoshi

doi:10.1002/hep.25932

Cited by 149 publications

(135 citation statements)

References 29 publications

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“…In human NASH-related HCC tissues, an upregulation of SCD1 was also found [6] . The expression of FASN was found to be downregulated with the MCD diet without differences among the genotypes, similar to other murine models of steatohepatitis [31,40] and human NASH [28] . We also found no changes for the lipolysis regulators PPARa and CPT1 in p62 transgenic mice.…”

Section: Esupporting

confidence: 79%

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Simon

Kessler

Gemperlein

et al. 2014

WJG

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AIM:To characterize how insulin-like growth factor 2 (IGF2 ) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol. METHODS:Non-alcoholic steatohepatitis (NASH) was induced in wild-type mice and in mice overexpressing p62 specifically in the liver by feeding the mice a methionine and choline deficient (MCD) diet for either two or four weeks. As a control, animals were fed a methionine and choline supplemented diet. Serum triglycerides, cholesterol, glucose, aspartate aminotransferase and alanine transaminase were determined by standard analytical techniques. Hepatic gene expression was determined by real-time reverse transcription-polymerase chain reaction. Generation of reactive oxygen species in liver tissue was quantified as thiobarbituric acid reactive substances using a photometric assay and malondialdehyde as a standard. Tissue fatty acid profiles and cholesterol levels were analyzed by gas chromatographymass spectrometry after hydrolysis. Hepatocellular iron accumulation was determined by Prussian blue staining in paraffin-embedded formalin-fixed tissue. Filipin staining on frozen liver tissue was used to quantify hepatic free cholesterol levels. Additionally, nuclear localization of the nuclear factor kappa B (NF-κB) subunit p65 was examined in frozen tissues. RESULTS:Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein 2-2 (IGF2BP2-2/IMP2-2/p62) induces steatosis with regular chow and amplifies NASH-induced fibrosis in the MCD mouse model. Activation of NF-κB and expression of NF-κB target genes suggested an increased inflammatory response in p62 transgenic animals. Analysis of hepatic lipid composition revealed an elevation of monounsaturated fatty acids as well as increased hepatic cholesterol. Moreover, serum cholesterol was significantly elevated in p62 transgenic mice. Dietary cholesterol represents a critical factor for the development of NASH from hepatic steatosis. Filipin staining revealed increased free cholesterol in p62 transgenic livers, which were not diet-derived. The mRNA levels of the rate-limiting enzyme for cholesterol synthesis 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase or HMGCR) were not significantly upregulated, potentially due to increased cholesterol biosynthesis via elevated sterol regulatory element binding transcription factor 2 (SREBF2 ) gene expression and increased iron deposition in transgenic animals. CONCLUSION:This study provides evidence that p62/IGF2BP2-2 drives the progression of NASH through elevation of hepatic iron deposition and increased production of hepatic free cholesterol.

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Section: Esupporting

confidence: 79%

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Simon

Kessler

Gemperlein

et al. 2014

WJG

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“…Most interestingly, animals overexpressing ELOVL6 also show increased liver triglycerides and at the same time reduced FASN expression ( 20 ). Therefore, fatty acid synthesis does not appear to be the pivotal step in p62-mediated steatosis development.…”

Section: Discussionmentioning

confidence: 98%

“…Also hepatitis (B/C) has been described to strongly alter hepatic lipid content and composition ( 15,16 ). Recently, the fatty acid elongase 6 (ELOVL6), which catalyzes the elongation of C16 to C18 fatty acids ( 17 ) and is a direct target of SREBF1 ( 18,19 ), has been shown to promote NASH in mice and humans and to be overexpressed in a murine NASH model ( 20,21 ). Interestingly, however, there is still a lack of understanding of the upstream signaling pathways that are responsible for SREBF1 activation and why elevated ELOVL6 increases total fatty acid production.…”

Section: Protein Isolation and Analysis By Western Blotmentioning

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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“…Such a favourable metabolic response to high-fat diet in Elovl6 À / À mice may be largely due to increased ratio of palmitoleic acid to palmitic acid (PA) in the liver. More recent study has shown that atherogenic high-fat-diet-induced hepatic inflammation, oxidative damage and fibrosis in the liver were attenuated in Elovl6 À / À mice, despite comparable hepatosteatosis in Elovl6 À / À and WT mice 18 . These data suggest that alteration of FA components in Elovl6 À / À mice contribute to insulin sensitivity independently of obesity, cellular energy balance and stress.…”

mentioning

confidence: 96%

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

et al. 2013

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Despite the established role of alveolar type II epithelial cells for the maintenance of pulmonary function, little is known about the deregulation of lipid composition in the pathogenesis of pulmonary fibrosis. The elongation of long-chain fatty acids family member 6 (Elovl6) is a rate-limiting enzyme catalysing the elongation of saturated and monounsaturated fatty acids. Here we show that Elovl6 expression is significantly downregulated after an intratracheal instillation of bleomycin (BLM) and in human lung with idiopathic pulmonary fibrosis. Elovl6-deficient (Elovl6 À / À ) mice treated with BLM exhibit severe fibroproliferative response and derangement of fatty acid profile compared with wild-type mice. Furthermore, Elovl6 knockdown induces a change in fatty acid composition similar to that in Elovl6 À / À mice, resulting in induction of apoptosis, TGF-b1 expression and reactive oxygen species generation. Our findings demonstrate a previously unappreciated role for Elovl6 in the regulation of lung homeostasis, and in pathogenesis and exacerbation of BLM-induced pulmonary fibrosis.

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Elovl6 promotes nonalcoholic steatohepatitis

Cited by 149 publications

References 29 publications

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

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

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

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