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

Adipose tissue dysfunction contributes to the pathogenesis of non-alcoholic steatohepatitis (NASH). The adapter protein alpha-syntrophin (SNTA) is expressed in adipocytes. Knock-down of SNTA increases preadipocyte proliferation and formation of small lipid droplets, which are both characteristics of healthy adipose tissue. To elucidate a potential protective role of SNTA in NASH, SNTA null mice were fed a methionine-choline-deficient (MCD) diet or an atherogenic diet which are widely used as preclinical NASH models. MCD diet mediated loss of fat mass was largely improved in SNTA?/? mice compared to the respective wild type animals. Hepatic lipids were mostly unchanged while the oxidative stress marker malondialdehyde was only induced in the wild type mice. The expression of inflammatory markers and macrophage immigration into the liver were reduced in SNTA?/? animals. This protective function of SNTA loss was absent in atherogenic diet induced NASH. Here, hepatic expression of inflammatory and fibrotic genes was similar in both genotypes though mutant mice gained less body fat during feeding. Hepatic cholesterol and ceramide were strongly induced in both strains upon feeding the atherogenic diet, while hepatic sphingomyelin, phosphatidylserine and phosphatidylethanolamine levels were suppressed.SNTA deficient mice are protected from fat loss and NASH in the experimental MCD model. NASH induced by an atherogenic diet is not influenced by loss of SNTA. The present study suggests the use of different experimental NASH models to study the pathophysiological role of proteins like SNTA in NASH.     

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

Molecular and Cellular Biochemistry - Non-alcoholic steatohepatitis (NASH) is a rapidly growing liver disease. The chemoattractant chemerin is abundant in hepatocytes, and hepatocyte expressed...     

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

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 Unpublished data from our group suggested that SNTA deficiency is associated with altered tubulin alpha 8 (TUBA8) levels in fat.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.