Lipid abnormalities in alpha/beta2-syntrophin null mice are independent from ABCA1

• Published in: Biochimica et biophysica acta Vol. 1851; no. 5; pp. 527 - 536
• Main Authors: Hebel, Tobias, Eisinger, Kristina, Neumeier, Markus, Rein-Fischboeck, Lisa, Pohl, Rebekka, Meier, Elisabeth M., Boettcher, Alfred, Froehner, Stanley C., Adams, Marvin E., Liebisch, Gerhard, Krautbauer, Sabrina, Buechler, Christa
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2015
• Subjects: Adipose Tissue, Brown - metabolism; Adiposity; Animals; ATP Binding Cassette Transporter 1 - metabolism; Blood Glucose - metabolism; Cell Line, Tumor; Cholesterol - blood; Diet, High-Fat; Disease Models, Animal; Dystrophin-Associated Proteins - deficiency; Dystrophin-Associated Proteins - genetics; Enzyme Activation; Genotype; Glucose Intolerance - blood; Glucose Intolerance - genetics; Glucose tolerance test; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Insulin; Insulin - blood; Intracellular Signaling Peptides and Proteins - metabolism; Lipids - blood; Liver; Liver - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1 - metabolism; Obesity - blood; Obesity - genetics; Obesity - metabolism; Obesity - physiopathology; Phenotype; Phosphoproteins - metabolism; Phosphorylation; Scavenger receptor B-I; Scavenger Receptors, Class B - metabolism; Sodium-Hydrogen Exchangers - metabolism; Sphingomyelin; Sphingomyelins - blood; Sterol Regulatory Element Binding Protein 2 - metabolism; Triglycerides - blood; Weight Gain; Sphingomyelin; Glucose tolerance test; Insulin; Scavenger receptor B-I; Liver
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2015.01.012

The syntrophins alpha (SNTA) and beta 2 (SNTB2) are molecular adaptor proteins shown to stabilize ABCA1, an essential regulator of HDL cholesterol. Furthermore, SNTB2 is involved in glucose stimulated insulin release. Hyperglycemia and dyslipidemia are characteristic features of the metabolic syndrome, a serious public health problem with rising prevalence. Therefore, it is important to understand the role of the syntrophins herein. Mice deficient for both syntrophins (SNTA/B2−/−) have normal insulin and glucose tolerance, hepatic ABCA1 protein and cholesterol. When challenged with a HFD, wild type and SNTA/B2−/− mice have similar weight gain, adiposity, serum and liver triglycerides. Hepatic ABCA1, serum insulin and insulin sensitivity are normal while glucose tolerance is impaired. Liver cholesterol is reduced, and expression of SREBP2 and HMG-CoA-R is increased in the knockout mice. Scavenger receptor-BI (SR-BI) protein is strongly diminished in the liver of SNTA/B2−/− mice while SR-BI binding protein NHERF1 is not changed and PDZK1 is even induced. Knock-down of SNTA, SNTB2 or both has no effect on hepatocyte SR-BI and PDZK1 proteins. Further, SR-BI levels are not reduced in brown adipose tissue of SNTA/B2−/− mice excluding that syntrophins directly stabilize SR-BI. SR-BI stability is regulated by MAPK and phosphorylated ERK2 is induced in the liver of the knock-out mice. Blockage of ERK activity upregulates hepatocyte SR-BI showing that increased MAPK activity contributes to low SR-BI. Sphingomyelin which is well described to regulate cholesterol metabolism is reduced in the liver and serum of the knock-out mice while the size of serum lipoproteins is not affected. Current data exclude a major function of these syntrophins in ABCA1 activity and insulin release but suggest a role in regulating glucose uptake, ERK and SR-BI levels, and sphingomyelin metabolism in obesity. •Mice deficient for alpha and beta 2 syntrophins have normal serum insulin.•Hepatic ABCA1 protein is similar to wild type mice.•Increased ERK1/2 seems to contribute to low hepatic SR-BI.•Sphingomyelin is reduced in the liver and serum of the knock-out mice.•Hepatic but not serum cholesterol is lower in the knock-out animals.