Effect of liver total sphingomyelin synthase deficiency on plasma lipid metabolism

Li, Zhiqiang; Chiang, Yeunpo; He, Mulin; Zhang, Ke; Zheng, Jiao; Wu, Weihua; Cai, Jiajia; Chen, Yong; Chen, Guangzhi; Chen, Yunqin; Dong, Jianyu; Worgall, Tilla S.

doi:10.1016/j.bbalip.2021.158898

Cited by 16 publications

(25 citation statements)

References 55 publications

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“…We previously demonstrated that disruption of liver Sms in 2- to 3-month-old mice results in a significant reduction of triglyceride-rich lipoprotein production ( Li et al, 2021 ). In addition, livers from 2-month-old Sms1/Sms2 KO mice appear to be normal, compared with those from 2-month-old WT and Sms2 KO mice ( Li et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we found that the levels of three glycosphingolipids [(GluCer, lactosylceramide, and monosialodihexosylganglioside(GM3)] are significantly increased in Sms1/Sms2 double KO, but not Sms2 KO, mouse hepatocytes, compared with controls ( Li et al, 2021 ). Here, we first confirmed that GluCer levels were indeed significantly increased in double KO mouse livers ( Figure 5 A).…”

Section: Resultsmentioning

confidence: 99%

“…We were unable to exclude the possibility that the observed pathology was related to other glycosphingolipids, such as lactosylceramide and GM3, which have also been shown to be increased in the double KO mouse liver ( Li et al, 2021 ). Lactosylceramide is enriched in the cell plasma membrane and may be involved in cell migration and phagocytosis ( Iwabuchi et al., 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation

Chiang

et al. 2021

iScience

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Summary Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1 /global Sms2 double-knockout (dKO) exhibited severe steatosis under a high-fat diet. Moreover, chow diet-fed ≥6-month-old dKO mice had liver impairment, inflammation, and fibrosis, compared with wild type and Sms2 KO mice. RNA sequencing showed 3- to 12-fold increases in various genes which are involved in lipogenesis, inflammation, and fibrosis. Further, we found that direct GluCer treatment ( in vitro and in vivo ) promoted hepatocyte to secrete more activated TGFβ1, which stimulated more collagen 1α1 production in hepatic stellate cells. Additionally, GluCer promoted more β-catenin translocation into the nucleus, thus promoting tumorigenesis. Importantly, human NASH patients had higher liver GluCer synthase and higher plasma GluCer. These findings implicated that GluCer accumulation is one of triggers promoting the development of NAFLD into NASH, then, fibrosis, and tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation

Chiang

et al. 2021

iScience

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“…Because it is not possible to obtain global Sms1/Sms2/Smsr tKO mice by simply crossing all three single global KO mice together, we crossed liver-specific Sms1 /global Sms2 dKO mice ( 15 ) with global Smsr KO mice ( 16 ), yielding liver-specific Sms1 KO/global Sms2 /global Smsr tKO mice. All animals are bred on a C57BL/6 genetic background.…”

Section: Methodsmentioning

confidence: 99%

“…To prove that SMS1 and SMS2 have PC-PLC activity in vivo, we depleted all three members of SMS gene family in mice. We established liver-specific Sms1/global Sms2 double knockout (dKO) mice (15) and crossed them with our global Smsr KO mice (16) to obtain liver-specific Sms1/global Sms2/global Smsr triple KO (tKO) mice. The dKO and the tKO mice have no detectible total SM synthase activity in their livers (Fig.…”

Section: Effect Of Sms Family Deficiency On Pc and Dag Metabolismmentioning

confidence: 99%

Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity

Chiang

Chen

et al. 2021

Journal of Biological Chemistry

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Many studies have confirmed the enzymatic activity of a mammalian phosphatidylcholine (PC) phospholipase C (PLC) (PC-PLC), which produces diacylglycerol (DAG) and phosphocholine through the hydrolysis of PC in the absence of ceramide. However, the protein(s) responsible for this activity have never yet been identified. Based on the fact that tricyclodecan-9-yl-potassium xanthate can inhibit both PC-PLC and sphingomyelin synthase (SMS) activities, and SMS1 and SMS2 have a conserved catalytic domain that could mediate a nucleophilic attack on the phosphodiester bond of PC, we hypothesized that both SMS1 and SMS2 might have PC-PLC activity. In the present study, we found that purified recombinant SMS1 and SMS2 but not SMS-related protein have PC-PLC activity. Moreover, we prepared liver-specific Sms1 /global Sms2 double-KO mice. We found that liver PC-PLC activity was significantly reduced and steady-state levels of PC and DAG in the liver were regulated by the deficiency, in comparison with control mice. Using adenovirus, we expressed Sms 1 and Sms 2 genes in the liver of the double-KO mice, respectively, and found that expressed SMS1 and SMS2 can hydrolyze PC to produce DAG and phosphocholine. Thus, SMS1 and SMS2 exhibit PC-PLC activity in vitro and in vivo .

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Sphingolipids and Cholesterol

2022

Advances in Experimental Medicine and Biology

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Effect of liver total sphingomyelin synthase deficiency on plasma lipid metabolism

Cited by 16 publications

References 55 publications

Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation

Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation

Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity

Sphingolipids and Cholesterol

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