Hepatic Remnant Lipoprotein Clearance by Heparan Sulfate Proteoglycans and Low-Density Lipoprotein Receptors Depend on Dietary Conditions in Mice

Abstract

Objective Chylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear. Approach and Results Triglyceride-rich lipoprotein clearance was measured in AlbCre+Ndst1f/f, Ldlr−/−, and AlbCre+Lrp1f/f mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all three receptors (AlbCre+Ndst1f/f Lrp1f/f Ldlr−/−) displayed dramatic hyperlipidemia (870 ± 270 mg triglyceride/dL; 1300 ± 350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels due to reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (~20-40 nm diameter), while LDLR and LRP1 clear larger particles (~40-60 nm diameter). Finally, we show that HSPGs play a major role in clearance of TRLs in mice fed normal chow or under postprandial conditions but appear to play a less significant role on a high fat diet. Conclusion These data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently from LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the three major hepatic TRL clearance receptors in mice.

ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors

“…In the liver, low-density lipoprotein receptors (LDLRs), LDLR-related protein 1 (LRP1), and heparan sulfate proteoglycan receptors (HSPGs), predominantly syndecan-1 (SDC1), mediate the endocytic clearance of TRL remnants (17,18). To examine whether hepatic clearance via these receptors contributed to an ApoC-III ASO-mediated reduction of plasma TGs, we administered the ApoC-III ASO for 4 weeks to mice lacking LDLR (Ldlr Figure 5A).…”

“…Given these findings, we proposed that the dominant mode of action of the ApoC-III ASO in mice is to remove the inhibiAs expected, animals fed a high-fat diet had elevated plasma cholesterol levels ( Figure 5D). Interestingly, a reduction of ApoC-III had variable effects on plasma cholesterol levels, reducing levels in Figure 9A and Supplemental Figure 6) were evaluated for their uptake by primary hepatocytes isolated from tory effect of ApoC-III on the clearance of TRLs through LDLR and LRP1, which act in a redundant manner with respect to TRL clearance (17,23 Figure 7). This suggested that the TRL preparations showed no significant differences in particles size or retinol composition, except for the reduction in ApoC-III content.…”

Postprandial dysmetabolism: Too early or too late?

“…39 Another factor contributing to postprandial hypertriglyceridemia is lack of hepatic receptors (HSPG, LDLR, LRP1), which interfere with the clearance of chylomicrons and VLDL from the circulation. 40 Of note, some of the hepatic lipoprotein remnant clearance receptors may interact with insulin. Specifically, it has been shown that insulin may stimulate the translocation of LRP1 to the plasma membrane, thus contributing to RLPs clearance.…”

microRNAs in lipoprotein and lipid metabolism: from biological function to clinical application

“…Lipoproteins present diverse sizes (7-1200 nm of diameter) and can be classified based on their respective density or electrophoretic mobility [47]. The exogenous lipoprotein pathway, which comprises the apoB48-containing lipoproteins, consists in dietary lipid transport from the intestine to energy-demanding tissues such as muscle, adipose tissue and the liver [46,[48][49][50][51][52][53]. The endogenous lipoprotein pathway, which comprises the apoB100-containing lipoproteins, allows the transport of lipids from the liver to peripheral tissues [46,[49][50][51][52][53][54][55].…”

“…The exogenous lipoprotein pathway, which comprises the apoB48-containing lipoproteins, consists in dietary lipid transport from the intestine to energy-demanding tissues such as muscle, adipose tissue and the liver [46,[48][49][50][51][52][53]. The endogenous lipoprotein pathway, which comprises the apoB100-containing lipoproteins, allows the transport of lipids from the liver to peripheral tissues [46,[49][50][51][52][53][54][55]. The reverse cholesterol pathway consists in the efflux of excess cholesterol from extrahepatic tissues to HDLs and its transport to the liver for metabolization and excretion into the bile in the intestine [56][57][58][59][60].…”