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.

Heritability and Genome-Wide Association Study of Plasma Cholesterol in Chinese Adult Twins

“…Further, MAP signaling pathways participated in lipid metabolism ( 76 ). Syntrophin Beta 2 ( SNTB2 ) suggestes a role in ERK and SR-BI level, and sphingomyelin metabolism in obesity and have been proved to affect the activity of ABCA1 by stabilizing ABCA1 protein, which affect the catabolism of LDL-C level ( 77 – 79 ). Fas Associated Factor 1 ( FAF1 ) also plays a key role in regulating the LDL-C level ( 69 – 71 ).…”

Overgrazing induces alterations in the hepatic proteome of sheep (Ovis aries): an iTRAQ-based quantitative proteomic analysis

“…NCKAP1 (NCK-associated protein 1) is an integral membrane protein that regulates actin cytoskeleton organization [ 47 ]. SNTB1 (beta-1-syntrophin) is a peripheral membrane protein that is associated with mediating high-density lipoprotein (HDL) metabolism in the liver [ 48 ]. This is consistent with the elevated AST and ALT serum levels in the OG group of this study, which may interfere with liver protection and normal hepatocytes structure.…”

LXR Agonism Upregulates the Macrophage ABCA1/Syntrophin Protein Complex That Can Bind ApoA-I and Stabilized ABCA1 Protein, but Complex Loss Does Not Inhibit Lipid Efflux

“…Indeed, a recent report assessed ABCA1 expression levels in the liver of the Syntrophin α 1−/−/ β 2−/− mice and found lower levels of the transporter; however, this trend did not reach significance, and suppression of the β 1-syntrophin was not reported. 28 The level of liver apoA-I protein also showed a downward trend, but interestingly, both apoA-I and ABCA1 mRNA levels showed an increasing trend, suggesting post-transcriptional effects leading to a lower level of protein expression. Likewise, in our Syntrophin α 1−/−/ β 2−/− macrophages, we found less cell surface and total ABCA1 expression, and this was associated with a more rapid turnover of the transporter.…”