Associations between SNPs in Intestinal Cholesterol Absorption and Endogenous Cholesterol Synthesis Genes with Cholesterol Metabolism

Single nucleotide polymorphisms (SNPs) have been associated with cholesterol metabolism and may partly explain large inter-individual variability in intestinal cholesterol absorption and endogenous cholesterol synthesis rates. This cross-sectional study therefore examined whether SNPs in genes encoding for proteins involved in intestinal cholesterol absorption (ABCG5, ABCG8, and NPC1L1) and endogenous cholesterol synthesis (CYP51A1, DHCR7, DHCR24, HMGCR, HSD17B7, LBR, and MSMO1) were associated with intestinal cholesterol absorption markers (total cholesterol (TC) standardized campesterol and sitosterol levels), an endogenous cholesterol synthesis marker (TC-standardized lathosterol levels), and serum low-density lipoprotein cholesterol (LDL-C) concentrations in a European cohort. ABCG5 (rs4245786) and the tag SNP ABCG8 (rs4245791) were significantly associated with serum campesterol and/or sitosterol levels. In contrast, NPC1L1 (rs217429 and rs217416) were significantly associated with serum lathosterol levels. The tag SNP in HMGCR (rs12916) and a SNP in LBR (rs12141732) were significantly associated with serum LDL-C concentrations. SNPs in the cholesterol absorption genes were not associated with serum LDL-C concentrations. SNPs in CYP51A1, DHCR24, HSD17B7, and MSMO1 were not associated with the serum non-cholesterol sterols and LDL-C concentrations. Given the variable efficiency of cholesterol-lowering interventions, the identification of SNPs associated with cholesterol metabolism could be a step forward towards personalized approaches.

Low-density lipoprotein receptor (LDL-R) suppresses endogenous cholesterol synthesis pathway to oppose gammaherpesvirus replication in primary macrophages

Gammaherpesviruses are ubiquitous pathogens that establish life-long infections in >95% of adults worldwide and are associated with several cancers. We showed that endogenous cholesterol synthesis supports gammaherpesvirus replication. However, the role of exogenous cholesterol exchange and signaling during infection remains poorly understood. Extracellular cholesterol is carried in the serum by several lipoproteins, including low-density lipoproteins (LDL). The LDL-receptor (LDL-R) mediates the endocytosis of these cholesterol-rich LDL particles into the cell, thereby supplying the cell with cholesterol. We found that LDL-R expression attenuates gammaherpesvirus replication during the early stages of the replication cycle, as evident by increased viral gene expression in LDL-R -/- primary macrophages. This was not observed in primary fibroblasts, indicating that the antiviral effects of LDL-R are cell type-specific. Increased viral gene expression in LDL-R -/- primary macrophages was due to increased activity of the endogenous cholesterol synthesis pathway. Intriguingly, despite type I interferon-driven increase in LDL-R mRNA levels in infected macrophages, protein levels of LDL-R continually decreased over the single cycle of viral replication. Thus, our study has uncovered an intriguing tug of war between the LDL-R-driven antiviral effect on cholesterol metabolism and the viral targeting of the LDL-R protein. Importance. LDL-R is a cell surface receptor that mediates the endocytosis of cholesterol-rich low density lipoproteins, allowing cells to acquire cholesterol exogenously. Several RNA viruses usurp LDL-R function to facilitate replication; however, the role of LDL-R in DNA virus infection remains unknown. Gammaherpesviruses are double-stranded DNA viruses that are associated with several cancers. Here, we show that LDL-R attenuates gammaherpesvirus replication in primary macrophages by decreasing endogenous cholesterol synthesis activity, a pathway known to support gammaherpesvirus replication. In response, LDL-R protein levels are decreased in infected cells to mitigate the antiviral effects, revealing an intriguing tug-of-war between the virus and the host.

Use of endogenous cholesterol and its metabolite as markers of cyp450 metabolic activity

This article analyzes the application of the method for determining the activity of CYP3A4 by determining the concentration of endogenous cholesterol and its metabolite/4-hydroxycholine in blood plasma. It also provides information on the convergence assessment of data obtained using alternative methods for determining the activity of the same CYP450 isoenzyme (CYP3A4) using different substrates: cholesterol and cortisol.

DNA nanotweezers for stabilizing and dynamically lighting up a lipid raft on living cell membranes and the activation of T cells

We report a DNA nanotweezer that recruits raft-associated lipids, proteins and possibly endogenous cholesterol on living cell membrane. The DNA nanotweezers could activate T cell proliferation in a nonspecific activation manner.