title: Lipid abnormalities in alpha/beta2-syntrophin null mice are independent from ABCA1.
abstract: 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.
authors.affiliation: Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hebel
authors.affiliation: Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Eisinger
authors.affiliation: Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Neumeier
authors.affiliation: Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rein-Fischboeck
authors.affiliation: Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Pohl
authors.affiliation: Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Meier
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Boettcher
authors.affiliation: Department of Physiology and Biophysics, University of Washington, WA, USA.
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Froehner
authors.affiliation: Department of Physiology and Biophysics, University of Washington, WA, USA.
authors.forename: Marvin E
authors.initials: ME
authors.lastname: Adams
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.affiliation: Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Krautbauer
authors.affiliation: Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany. Electronic address: christa.buechler@klinik.uni-regensburg.de.
authors.forename: Christa
authors.initials: C
authors.lastname: Buechler
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D049029:Dystrophin-Associated Proteins / Q000172:deficiency* / Q000235:genetics; D004789:Enzyme Activation; D005838:Genotype; D018149:Glucose Intolerance / Q000097:blood / Q000235:genetics; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013109:Sphingomyelins / Q000097:blood; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001786:Blood Glucose; D002784:Cholesterol; D049029:Dystrophin-Associated Proteins; D006903:Hydroxymethylglutaryl CoA Reductases; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D010750:Phosphoproteins; D051122:Scavenger Receptors, Class B; D017923:Sodium-Hydrogen Exchangers; D013109:Sphingomyelins; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; C577833:Abca1 protein, mouse; C514896:PDZK1 protein, mouse; C454739:Scarb1 protein, mouse; C497391:Srebf2 protein, mouse; C093376:sodium-hydrogen exchanger regulatory factor; C091824:syntrophin; C535148:Mapk1 protein, mouse
keywords: Glucose tolerance test; Insulin; Liver; Scavenger receptor B-I; Sphingomyelin