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Sphingomyelin synthase 2 activity and liver steatosis: an effect of ceramide-mediated peroxisome proliferator-activated receptor ?2 suppression.

ABSTRACT: OBJECTIVE:Sphingolipid de novo biosynthesis is related to nonalcoholic fatty liver disease or hepatic steatosis. However, the mechanism is still unclear. Sphingomyelin synthase (SMS), using ceramide as one of the substrates to produce sphingomyelin, sits at the crossroads of sphingolipid biosynthesis. SMS has 2 isoforms: SMS1 and SMS2. SMS2 is the major isoform in liver. APPROACH AND RESULTS:To investigate the relationship between liver SMS2 activity-mediated sphingolipid changes and hepatic steatosis, we used 2 mouse models: Sms2 liver-specific transgenic and Sms2 knockout mice. We found that Sms2 liver-specific transgenic livers have lower ceramide and higher sphingomyelin, whereas Sms2 knockout livers have higher ceramide and lower sphingomyelin. We also found that liver Sms2 overexpression promoted fatty acid uptake and liver steatosis, whereas Sms2 deficiency had an opposite effect in comparison with their respective controls. Importantly, the exogenous ceramide supplementation to Huh7 cells, a human hepatoma cell line, reduced the expression of peroxisome proliferator-activated receptor ?2 and its target genes, Cd36 and Fsp27. Peroxisome proliferator-activated receptor ? reporter analysis confirmed this phenomenon. Furthermore, peroxisome proliferator-activated receptor ? antagonist treatment significantly decreased triglyceride accumulation in Sms2 liver-specific transgenic liver. CONCLUSIONS:We attributed these effects to ceramide that can suppress peroxisome proliferator-activated receptor ?2, thus reducing the expression of Cd36 and Fsp27 and reducing liver steatosis. After all, SMS2 inhibition in the liver could diminish liver steatosis.

SUBMITTER: Li Y

PROVIDER: S-EPMC3784343 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Sphingomyelin synthase 2 activity and liver steatosis: an effect of ceramide-mediated peroxisome proliferator-activated receptor γ2 suppression.

Li Yue Y Dong Jibin J Ding Tingbo T Kuo Ming-Shang MS Cao Guoqing G Jiang Xian-Cheng XC Li Zhiqiang Z

Arteriosclerosis, thrombosis, and vascular biology 20130502 7

<h4>Objective</h4>Sphingolipid de novo biosynthesis is related to nonalcoholic fatty liver disease or hepatic steatosis. However, the mechanism is still unclear. Sphingomyelin synthase (SMS), using ceramide as one of the substrates to produce sphingomyelin, sits at the crossroads of sphingolipid biosynthesis. SMS has 2 isoforms: SMS1 and SMS2. SMS2 is the major isoform in liver.<h4>Approach and results</h4>To investigate the relationship between liver SMS2 activity-mediated sphingolipid changes ...[more]

PMID: 23640498

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Project description:Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to explore the possible mechanisms involved. To that end, C57Bl/6 mice rendered obese and steatotic by chronic high-fat feeding were treated for 1 week with clodronate liposomes, which cause depletion of Kupffer cells. Loss of expression of marker genes Cd68, F4/80, and Clec4f, and loss of Cd68 immunostaining verified almost complete removal of Kupffer cells from the liver. Also, expression of complement components C1, the chemokine (C-C motif) ligand 6 (Ccl6), and cytokines interleukin-15 (IL-15) and IL-1beta were markedly reduced. Importantly, Kupffer cell depletion significantly decreased liver triglyceride and glucosylceramide levels concurrent with increased expression of genes involved in fatty acid oxidation including peroxisome proliferator-activated receptor alpha (PPARalpha), carnitine palmitoyltransferase 1A (Cpt1alpha), and fatty acid transport protein 2 (Fatp2). Treatment of mice with IL-1beta decreased expression of PPARalpha and its target genes, which was confirmed in primary hepatocytes. Consistent with these data, IL-1beta suppressed human and mouse PPARalpha promoter activity. Suppression of PPARalpha promoter activity was recapitulated by overexpression of nuclear factor kappaB (NF-kappaB) subunit p50 and p65, and was abolished upon deletion of putative NF-kappaB binding sites. Finally, IL-1beta and NF-kappaB interfered with the ability of PPARalpha to activate gene transcription. CONCLUSION: Our data point toward important cross-talk between Kupffer cells and hepatocytes in the regulation of hepatic triglyceride storage. The effect of Kupffer cells on liver triglycerides are at least partially mediated by IL-1beta, which suppresses PPARalpha expression and activity. Expression profiling of livers from mice fed control, low-fat diet diet or high-fat diet for 20weeks with or without knockdown of Kupffer cells.

Dataset Information

Sphingomyelin synthase 2 activity and liver steatosis: an effect of ceramide-mediated peroxisome proliferator-activated receptor ?2 suppression.

Publications

Sphingomyelin synthase 2 activity and liver steatosis: an effect of ceramide-mediated peroxisome proliferator-activated receptor γ2 suppression.

Similar Datasets

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