Scavenger Receptor BI Plays a Role in Facilitating Chylomicron Metabolism

Abstract

The function of scavenger receptor class B type I (SR-BI) in mediating the selective uptake of high density lipoprotein (HDL) cholesterol esters is well established. However, the potential role of SR-BI in chylomicron and chylomicron remnant metabolism is largely unknown. In the present investigation, we report that the cell association of 160 nm-sized triglyceride-rich chylomicronlike emulsion particles to freshly isolated hepatocytes from SR-BI-deficient mice is greatly reduced (>70%), as compared with wild-type littermate mice. Competition experiments show that the association of emulsion particles with isolated hepatocytes is efficiently competed for (>70%) by the well established SR-BI ligands, HDL and oxidized low density lipoprotein (LDL), whereas LDL is ineffective. Upon injection into SR-BI-deficient mice the hepatic association of emulsion particles is markedly decreased (ϳ80%) as compared with wild-type mice. The relevance of these findings for in vivo chylomicron (remnant) metabolism was further evaluated by studying the effect of SR-BI deficiency on the intragastric fat load-induced postprandial triglyceride response. The postprandial triglyceride response is 2-fold higher in SR-BI-deficient mice as compared with wild-type littermates (area-under-the-curve 39.6 ؎ 1.2 versus 21.1 ؎ 3.6; p < 0.005), with a 4-fold increased accumulation of chylomicron (remnant)-associated triglycerides in plasma at 6 h after intragastric fat load. We conclude that SR-BI is important in facilitating chylomicron (remnant) metabolism and might function as an initial recognition site for chylomicron remnants whereby the subsequent internalization can be exerted by additional receptor systems like the LDL receptor and LDL receptor-related protein. Chylomicrons are triglyceride (TG)1 -rich lipoproteins that transport dietary lipids from the intestine to the liver. Upon entering the circulation, chylomicrons are converted to remnants by the TG-hydrolyzing action of lipoprotein lipase (LPL) and the acquisition of apolipoproteins (apo) such as apoE. Chylomicron remnants are subsequently taken up by the liver by an apoE-mediated process (reviewed in Refs. 1-3). The essential role of apoE in remnant clearance was indicated by the accumulation of remnants in apoE-deficient mice (4). It has been suggested that several apoE-dependent recognition sites contribute to the removal of remnants, including the low-density lipoprotein (apoB and -E) receptor (LDLr) (4 -9), and the LDLr-related protein/␣ 2 -macroglobulin receptor (LRP) (8, 10, 11). It is generally accepted, however, that for the initial liver recognition of remnants, the so-called "capture step," additional systems are needed. The initial sequestration step was suggested to involve heparan sulfate proteoglycans (5, 12), the lipolysis-stimulated receptor (13-15), a TG-rich lipoprotein receptor (16, 17), the asialoglycoprotein receptor (18), LPL (19), and/or hepatic lipase (20), while we also provided evidence for a specific remnant receptor (21-23) to function as an initial re...

Scavenger receptor BI facilitates the metabolism of VLDL lipoproteins in vivo

“…The observed increase in VLDL cholesterol levels in the absence of SR-BI was not caused by an increased VLDL secretion rate or decreased expression of the LDLR or LRP-1, suggesting a direct involvement of SR-BI in the catabolism of VLDL. Interestingly, the postprandial triglyceride response after an intragastric fat load is higher in the absence of SR-BI, indicating that chylomicron metabolism also is altered in SR-BI-deficient mice (37). Furthermore, a common single nucleotide polymorphism in exon 8 (C 1050 YT) of CLA-1, the human homolog of SR-BI, was associated with lower LDL cholesterol levels in women, whereas several studies on common polymorphisms of CLA-1 have shown that some SR-BI variants interfere with the metabolism of apoB lipoproteins in humans, although the effects vary with age and gender (43)(44)(45)(46).…”

“…The serum decay and liver uptake of b-VLDL was determined in SR-BI 2/2 mice and wild-type SR-BI 1/1 littermates as described previously (36,37). Briefly, mice were anesthetized by subcutaneous injection of ketamine (60 mg/kg; Eurovet), fentanyl citrate, and fluanisone (1.26 mg/kg and 2 mg/kg, respectively; Janssen).…”

CD36 Mediates Both Cellular Uptake of Very Long Chain Fatty Acids and Their Intestinal Absorption in Mice

“…Expression of a different class B scavenger receptor, the HDL receptor SR-BI encoded by pSG5(mSR-BI), had no significant effect on either V 24:0 or V 16:0 (Fig. 2, hatched bars), even though SR-BI is also implicated in intestinal fat absorption/processing (15,16) and is structurally related to CD36. To control for scavenger receptor-dependent differences in cell surface expression, we measured HDL binding in cells transfected with either CD36 or SR-BI.…”

Phosphatidylinositol-3-Kinase Regulates Scavenger Receptor Class B Type I Subcellular Localization and Selective Lipid Uptake in Hepatocytes

“…3,13 In addition to functioning in the liver as an HDL receptor, SR-BI also contributes to the metabolism of chylomicron remnants. 14 Several reports have demonstrated an SR-BI-dependent activation of phosphatidylinositol-3-kinase (PI3K), by HDL. 15,16 PI3K is an extensively studied signaling molecule which is known to play a key role in a wide range of biological processes.…”