Alpha-syntrophin null mice are protected from non-alcoholic steatohepatitis in the methionine-choline-deficient diet model but not the atherogenic diet model

Rein-Fischboeck, Lisa; Haberl, Elisabeth M.; Pohl, Rebekka; Schmid, Verena; Feder, Susanne; Krautbauer, Sabrina; Liebisch, Gerhard; Buechler, Christa

doi:10.1016/j.bbalip.2018.02.006

Cited by 10 publications

(20 citation statements)

References 60 publications

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“…Consistently, MCD diet induced hepatic triglyceride accumulation in different studies. However, NASH-associated changes of further lipid classes were less reproducible [17–19].…”

Section: Introductionmentioning

confidence: 99%

“…In NASH, hepatocytes displaying cholesterol crystals activated circumjacent Kupffer cells and thus contributed to disease progression [20]. In mice fed a MCD chow, liver cholesterol was increased in some but not all models [18, 19]. The ratio of hepatic phosphatidylcholine (PC) to phosphatidylethanolamine (PE) is important for membrane integrity and liver health, and was decreased in NASH [21].…”

Section: Introductionmentioning

confidence: 99%

“…The ratio of hepatic phosphatidylcholine (PC) to phosphatidylethanolamine (PE) is important for membrane integrity and liver health, and was decreased in NASH [21]. Not all studies could identify reduced phosphatidylcholine in the liver of MCD diet fed rodents [17–19, 22].…”

Section: Introductionmentioning

confidence: 99%

“…Particular ceramide species are cytotoxic and contribute to liver cell death [23]. After all, hepatic ceramide levels were unchanged or induced in the liver of MCD diet fed mice [18, 19, 22]. High, low and normal sphingomyelin levels were detected in NASH liver [18, 19, 22].…”

Section: Introductionmentioning

confidence: 99%

“…After all, hepatic ceramide levels were unchanged or induced in the liver of MCD diet fed mice [18, 19, 22]. High, low and normal sphingomyelin levels were detected in NASH liver [18, 19, 22]. In summary, results regarding changes of hepatic lipids in the different MCD models were inconsistent [17, 18, 22, 24].…”

Section: Introductionmentioning

confidence: 99%

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Variations in hepatic lipid species of age-matched male mice fed a methionine-choline-deficient diet and housed in different animal facilities

et al. 2019

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Background: Non-alcoholic steatohepatitis (NASH) is a common disease and feeding mice a methionine-cholinedeficient (MCD) diet is a frequently used model to study its pathophysiology. Genetic and environmental factors influence NASH development and liver lipid content, which was studied herein using C57BL/6 J mice bred in two different animal facilities. Methods: Age-matched male C57BL/6 J mice bred in two different animal facilities (later on referred to as WT1 and WT2) at the University Hospital of Regensburg were fed identical MCD or control chows for 2 weeks. Hepatic gene and protein expression and lipid composition were determined. Results: NASH was associated with increased hepatic triglycerides, which were actually higher in WT1 than WT2 liver in both dietary groups. Cholesterol contributes to hepatic injury but was only elevated in WT2 NASH liver. Ceramides account for insulin resistance and cell death, and ceramide species d18:1/16:0 and d18:1/18:0 were higher in the NASH liver of both groups. Saturated sphingomyelins only declined in WT1 NASH liver. Lysophosphatidylcholine concentrations were quite normal in NASH and only one of the 12 altered phosphatidylcholine species declined in NASH liver of both groups. Very few phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol species were comparably regulated in NASH liver of both animal groups. Seven of these lipid species declined and two increased in NASH. Notably, hepatic mRNA expression of proinflammatory (F4/80, CD68, IL-6, TNF and chemerin) and profibrotic genes (TGF beta and alpha SMA) was comparable in WT1 and WT2 mice.Conclusions: Mice housed and bred in different animal facilities had comparable disease severity of NASH whereas liver lipids varied among the groups. Thus, there was no specific lipid signature for NASH in the MCD model.

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“…Consistently, MCD diet induced hepatic triglyceride accumulation in different studies. However, NASH-associated changes of further lipid classes were less reproducible [17–19].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Variations in hepatic lipid species of age-matched male mice fed a methionine-choline-deficient diet and housed in different animal facilities

et al. 2019

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Hepatocyte expressed chemerin-156 does not protect from experimental non-alcoholic steatohepatitis

et al. 2022

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Non-alcoholic steatohepatitis (NASH) is a rapidly growing liver disease. The chemoattractant chemerin is abundant in hepatocytes, and hepatocyte expressed prochemerin protected from NASH. Prochemerin is inactive and different active isoforms have been described. Here, the effect of hepatocyte expressed muChem-156, a highly active murine chemerin isoform, was studied in the methionine–choline deficient dietary model of NASH. Mice overexpressing muChem-156 had higher hepatic chemerin protein. Serum chemerin levels and the capability of serum to activate the chemerin receptors was unchanged showing that the liver did not release active chemerin. Notably, activation of the chemerin receptors by hepatic vein blood did not increase in parallel to total chemerin protein in patients with liver cirrhosis. In experimental NASH, muChem-156 had no effect on liver lipids. Accordingly, overexpression of active chemerin in hepatocytes or treatment of hepatocytes with recombinant chemerin did not affect cellular triglyceride and cholesterol levels. Importantly, overexpression of muChem-156 in the murine liver did not change the hepatic expression of inflammatory and profibrotic genes. The downstream targets of chemerin such as p38 kinase were neither activated in the liver of muChem-156 producing mice nor in HepG2, Huh7 and Hepa1-6 cells overexpressing this isoform. Recombinant chemerin had no effect on global gene expression of primary human hepatocytes and hepatic stellate cells within 24 h of incubation. Phosphorylation of p38 kinase was, however, increased upon short-time incubation of HepG2 cells with chemerin. These findings show that muChem-156 overexpression in hepatocytes does not protect from liver steatosis and inflammation.

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Alpha-syntrophin dependent expression of tubulin alpha 8 protein in hepatocytes

et al. 2018

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The scaffold protein alpha-syntrophin (SNTA) is a component of the dystrophin glycoprotein complex and has been comprehensively studied in skeletal muscle and adipocytes. SNTA is further expressed in the liver where its biological role remains unclear. Unpublished data from our group suggested that SNTA deficiency is associated with altered tubulin alpha 8 (TUBA8) levels in fat. TUBA8 is highly expressed in different cell lines including hepatoma cells, and here we analyzed whether SNTA has a role herein. In Hepa1-6 cells, TUBA8 protein levels were increased upon SNTA knock down and were reduced upon overexpression of SNTA. This regulation was not identified when analyzing mRNA expression. In the liver of SNTA-deficient mice, TUBA8 protein was higher compared to the respective wild-type controls while RNA expression was even suppressed. Using the HaloTag platform, TUBA8 was found to form a complex with SNTA in Hepa1-6 cells. In the hepatic stellate cell line LX-2, the lack or overexpression of SNTA did, however, not change TUBA8 protein expression. SNTA and TUBA8 are described to regulate cell proliferation. Yet, knock down of SNTA did neither affect proliferation nor viability of Hepa1-6 cells. The present study shows that SNTA protein levels are inversely related to TUBA8 protein expression in the hepatocyte cell line Hepa1-6.

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Alpha-syntrophin null mice are protected from non-alcoholic steatohepatitis in the methionine-choline-deficient diet model but not the atherogenic diet model

Cited by 10 publications

References 60 publications

Variations in hepatic lipid species of age-matched male mice fed a methionine-choline-deficient diet and housed in different animal facilities

Variations in hepatic lipid species of age-matched male mice fed a methionine-choline-deficient diet and housed in different animal facilities

Hepatocyte expressed chemerin-156 does not protect from experimental non-alcoholic steatohepatitis

Alpha-syntrophin dependent expression of tubulin alpha 8 protein in hepatocytes

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