Abstract
Hepatic uptake of triglyceride-rich remnant lipoproteins is mediated by the low-density lipoprotein receptor, a low-density lipoprotein receptor related protein and the heparan sulfate proteoglycan, syndecan-1. Heparan sulfate proteoglycan also mediates low-density lipoprotein receptor degradation by a regulator of cholesterol homeostasis, proprotein convertase subtilisin kexin type 9 (PCSK9), thereby hampering triglyceride-rich remnant lipoproteins uptake. In this study, we investigated the effects of proteinuria on PCSK9, hepatic heparan sulfate proteoglycan and plasma triglyceride-rich remnant lipoproteins. Adriamycin-injected rats developed proteinuria, elevated triglycerides and total cholesterol (all significantly increased). Proteinuria associated with triglycerides and total cholesterol and serum PCSK9 (all significant associations) without loss of the low-density lipoprotein receptor as evidenced by immunofluorescence staining and western blotting. In proteinuric rats, PCSK9 accumulated in sinusoids, whereas in control rats PCSK9 was localized in the cytoplasm of hepatocytes. Molecular profiling revealed that the heparan sulfate side chains of heparan sulfate proteoglycan to be hypersulfated in proteinuric rats. Competition assays revealed sulfation to be a major determinant for PCSK9 binding. PCSK9 partly colocalized with hypersulfated heparan sulfate in proteinuric rats, but not in control rats. Hence, proteinuria induces hypersulfated hepatic heparan sulfate proteoglycans, increasing their affinity to PCSK9. This might impair hepatic triglyceride-rich remnant lipoproteins uptake, causing proteinuria-associated dyslipidemia. Thus, our study reveals PCSK9/heparan sulfate may be a novel target to control dyslipidemia.
Highlights
Hepatic uptake of triglyceride-rich remnant lipoproteins is mediated by the low-density lipoprotein receptor, a lowdensity lipoprotein receptor related protein and the heparan sulfate proteoglycan, syndecan-1
Proteinuria does not affect the protein expression of hepatic lipoprotein receptors Because low-density lipoprotein receptor (LDLR), LRP-1, and syndecan-1 are the major hepatic receptors for VLDL and LDL, we studied their expression by immunofluorescence staining, quantitative reverse transcriptase–polymerase chain reaction, and Western blot or dot blotting (Figure 2)
We found that dyslipidemia in proteinuric rats is associated with hypersulfation of hepatic Heparan sulfate (HS) along with sinusoidal accumulation of proprotein convertase subtilisin kexin type 9 (PCSK9), without changes in LDLR protein levels
Summary
Hepatic uptake of triglyceride-rich remnant lipoproteins is mediated by the low-density lipoprotein receptor, a lowdensity lipoprotein receptor related protein and the heparan sulfate proteoglycan, syndecan-1. Proteinuria induces hypersulfated hepatic heparan sulfate proteoglycans, increasing their affinity to PCSK9 This might impair hepatic triglyceride-rich remnant lipoproteins uptake, causing proteinuria-associated dyslipidemia. We discovered that proteinuria induces hypersulfation of hepatic heparan sulfate proteoglycans, increasing their affinity to proprotein convertase subtilisin kexin type 9 (PCSK9) and causing sinusoidal accumulation of PCSK9. These changes were associated with elevated plasma triglycerides and total cholesterol, without affecting lowdensity lipoprotein receptor expression. These data indicate a novel mechanism behind dyslipidemia in chronic kidney disease. The reduced clearance of triglyceride-rich remnant lipoproteins due to hepatic loss of syndecan-1, low-density lipoprotein receptor (LDLR)–related protein (LRP-1), and/or LDLR is reported.[12,13,14,15,16,17]
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