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Atherosclerosis
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Recent findings showed that a receptor, bound to the surface of cells, mediates the uptake of LDL and extended the role of lipoprotein receptors into the degradation of other lipoproteins.563,564 These receptors regulate plasma lipoprotein concentrations, serve as a target for cholesterol delivery into cells, and play part in the homeostasis of cholesterol.231,387,388 Three receptors have been identified: (1) the apoB-E receptor, that binds LDL and apoE containing HDL and occurs in hepatocytes and certain peripheral tissues,308,551 (2) the apoE receptor, which does not bind normal LDL, but interacts with chylomicron remnants and HDL containing apoE;305,307 and (3) the (3-VLDL receptor of macrophages, which plays a role in tissue levels of cholesterol, connected with the early stages of atherosclerosis and with xanthoma formation.253
Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia
Published in Expert Opinion on Drug Safety, 2022
Yajnavalka Banerjee, Anca Pantea Stoian, Arrigo Francesco Giuseppe Cicero, Federica Fogacci, Dragana Nikolic, Alexandros Sachinidis, Ali A. Rizvi, Andrej Janez, Manfredi Rizzo
Also, the fact that inclisiran reduces intracellular PCSK9 rather than extracellular PCSK9 could have additional benefits in lipid metabolism. Several studies show that the PCSK9 function extends beyond the regulation of LDL-C levels. One of these aspects is the ability of PCSK9 to modulate the levels of triglyceride rich lipoproteins VLDL and intermediate-density lipoprotein (IDL) particles. However, the available data in this domain are contradictory and to some extent inconclusive. Plasma PCSK9 levels appear to correlate with triglycerides, VLDL, and IDL-C in majority of investigations [59]. Interplay of several mechanisms such as a) increased apoB48 production in the enterocytes with concomitant increase in the secretion of chylomicrons, b) impaired degradation of apoB through autophagy leading to its boosted synthesis, c) augmented VLDL secretion from the hepatocytes, d) reduced uptake of triglyceride rich lipoproteins by LDLR, and e) reduction in the density of other lipoprotein receptors (such as VLDL receptor, CD36, apoE receptor, and LRP1) leading to reduced receptor uptake of triglyceride-rich lipoproteins is involved in the regulation of triglyceride-rich lipoprotein levels by PCSK9 [60].
An evaluation of roxadustat for the treatment of anemia associated with chronic kidney disease
Published in Expert Opinion on Pharmacotherapy, 2022
Yu Kurata, Tetsuhiro Tanaka, Masaomi Nangaku
Elevated low-density lipoprotein (LDL) cholesterol is an established risk factor for CV disease [59]. In clinical trials, roxadustat decreased low-density lipoprotein (LDL) cholesterol levels compared with placebo or ESAs in both NDD and DD patients (Table 3). This effect on lipids has only been observed with some HIF-PHIs (e.g. daprodustat [60,61] and desidustat [62]) and is presumably dependent on the characteristics such as PK and PD of each drug. Although the precise mechanism remains unclear, a possible explanation for lowering LDL includes upregulation of very-low-density lipoprotein (VLDL) receptor [63] and downregulation of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase via insulin-induced gene 2 upregulation [64]. Of note, roxadustat also decreased HDL cholesterol levels in some clinical trials, and reduced HDL may cancel out the impact of LDL lowering on CV risk. Although recent in vivo studies showed HIF-PHIs mitigated obesity-related organ damages and atherosclerosis in mice fed with high-fat diet [65,66], further clinical studies will be needed to evaluate whether roxadustat is beneficial in obese patients via its effects on lipids.
Low-density lipoprotein nanomedicines: mechanisms of targeting, biology, and theranostic potential
Published in Drug Delivery, 2021
The uptake of LDL occurs via receptor-mediated endocytosis by a family of structurally similar LDL receptor proteins that includes LDL receptor-related protein (LRP or megalin), very-low density lipoprotein (vLDL) receptor, and apolipoprotein E receptor-2 (ApoER2) (May et al., 2007). While it was originally thought that lipids were the only ligands bound by the LDL receptor family, it has since been shown that LRP is a scavenger receptor that binds to proteases, lipases, protease inhibitors, and exotoxin A from a bacterium (Figure 1) (Willnow et al., 1999). Therefore LRP and other members of this receptor family are involved in various biological processes unrelated to lipoprotein metabolism (Herz & Strickland, 2001).