Intestinal SR-BI is upregulated in insulin-resistant states and is associated with overproduction of intestinal apoB48-containing lipoproteins

Abstract

Intestinal lipid dysregulation is a common feature of insulin-resistant states. The present study investigated alterations in gene expression of key proteins involved in the active absorption of dietary fat and cholesterol in response to development of insulin resistance. Studies were conducted in two diet-induced animal models of insulin resistance: fructose-fed hamster and high-fat-fed mouse. Changes in the mRNA abundance of lipid transporters, adenosine triphosphate cassette (ABC) G5, ABCG8, FA-CoA ligase fatty acid translocase P4, Niemann-Pick C1-Like1 (NPC1L1), fatty acid transport protein 4 (FATP4), and Scavenger Receptor Class B Type I (SR-BI), were assessed in intestinal fragments (duodenum, jejunum, and ileum) using quantitative real-time PCR. Of all the transporters evaluated, SR-B1 showed the most significant changes in both animal models examined. A marked stimulation of SR-B1 expression was observed in all intestinal segments examined in both insulin-resistant animal models. The link between SR-BI expression and intestinal lipoprotein production was then examined in the Caco-2 cell model. SR-B1 overexpression in Caco-2 cells increased apolipoprotein B (apoB) 100 and apoB48 secretion, whereas RNAi knock down of SR-B1 decreased secretion of both apoB100 and apoB48. We also observed changes in subcellular distribution of SR-B1 in response to exogenous lipid and insulin. Confocal microscopy revealed marked changes in SR-BI subcellular distribution in response to both exogenous lipids (oleate) and insulin. In summary, marked stimulation of intestinal SR-BI occurs in vivo in animal models of diet-induced insulin resistance, and modulation of SR-BI in vitro regulates production of apoB-containing lipoprotein particles. We postulate that apical and/or basolateral SR-BI may play an important role in intestinal chylomicron production and may contribute to chylomicron overproduction normally observed in insulin-resistant states.

Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice

“…Although several groups have hypothesized a role for SR-BI in intestinal cholesterol absorption ( 36,55,56,59,65 ), studies where cholesterol absorption was actually quantifi ed in mouse models of SR-BI defi ciency ( 57 ) and now transgenic overexpression ( Figs. 1, 2 , 4) have not supported such a role.…”

“…Several laboratories have previously proposed a role for SR-BI as a high-affi nity receptor for cholesterol at the brush border membrane ( 55,56 ), as well as a mechanism by which cholesterol is traffi cked from the intestinal lumen across the enterocyte in an apical to basolateral pattern for packaging into chylomicrons ( 36,55,56,59,65 ). Further, intestinal SR-BI has been linked to overproduction of chylomicrons in insulin-resistant states ( 65 ).…”

“…Further, intestinal SR-BI has been linked to overproduction of chylomicrons in insulin-resistant states ( 65 ). However, the majority of cell-based work examining the subcellular traffi cking with this directional traffi cking pattern in polarized cells, hepatic overexpression or knockout of SR-BI either promotes or diminishes the movement of HDL-derived cholesterol into bile, respectively ( 37,(42)(43)(44)49 ).…”

Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation

“…Epidemiological studies have linked elevated plasma insulin and reduced spontaneous apoptosis in normal colonic epithelium to risk of precancerous colorectal adenomas (Keku et al, 2005). A small but mounting body of evidence suggests that obesity and type-2 diabetes are associated with insulin resistance at the level of the enterocyte, which might promote aberrant lipid handling and exacerbate dyslipidemia, (Federico et al, 2006;Haidari et al, 2002;Hayashi et al, 2011). Despite this evidence for potential roles of insulin in aberrant cell growth, survival or dysfunction of differentiated enterocytes, little is known about the expression or specific functions of the IR, and particularly IR-A and IR-B isoforms in the intestinal epithelium.…”

Loss of liver FA binding protein significantly alters hepatocyte plasma membrane microdomains

“…5D, I ), but not in homogenate. Although SR-B1 was much lower in the plasma membrane subfractions than hepatocyte homogenate, probably due to localization in intracellular membrane vesicles ( 9,42,43 ), SR-B1 was enriched >8-fold in the cholesterol-rich versus cholesterol-poor microdomains of wild-type hepatocyte plasma membranes ( Fig. 5E, J ) and 2-fold in the L-FABP-null hepatocytes.…”