Can modulators of apolipoproteinB biogenesis serve as an alternate target for cholesterol-lowering drugs?

Abstract

Understanding the molecular defects underlying cardiovascular disease is necessary for the development of therapeutics. The most common method to lower circulating lipids, which reduces the incidence of cardiovascular disease, is statins, but other drugs are now entering the clinic, some of which have been approved. Nevertheless, patients cannot tolerate some of these therapeutics, the drugs are costly, and/or the treatments are approved for only rare forms of disease. Efforts to find alternative treatments have focused on other factors, such as apolipoproteinB (apoB), which transports cholesterol in the blood stream. The levels of apoB are regulated by endoplasmic reticulum (ER) associated degradation as well as by a post ER degradation pathway in model systems, and we suggest that these events provide novel therapeutic targets. We discuss first how cardiovascular disease arises and how cholesterol is regulated, and then summarize the mechanisms of action of existing treatments for cardiovascular disease. We then review the apoB biosynthetic pathway, focusing on steps that might be amenable to therapeutic interventions.

Cholesterol Metabolism: A Potential Therapeutic Target in Glioblastoma

“…Triacylglycerol in the chylomicrons is hydrolyzed by lipoprotein lipase in blood vessels, and the cholesterol left behind in the chylomicron remnants are taken up and utilized by the liver [60,61]. The cholesterol from liver and dietary origins can be packed into particles of very low-density lipoproteins (VLDLs), which leave the liver and transport cholesterol to other tissues [62]. Another difference between liver and brain cholesterol metabolism is that cholesterol can be recycled through enterohepatic circulation, which does not exist in the brain (Figure 2).…”

Hsp104 facilitates the endoplasmic‐reticulum–associated degradation of disease‐associated and aggregation‐prone substrates

“…ApoB is the major proteinaceous component in chylomicrons and low‐density lipoproteins (LDLs) and is a large (~540 kDa), amphipathic protein produced in two isoforms: full length ApoB (ApoB100) and an isoform that is ~48% of the full‐length protein (ApoB48). ApoB100 is synthesized in the liver, enters the ER cotranslationally, becomes incorporated into LDLs, and is secreted into the serum when excess hepatic lipids are available . ApoB48 is instead synthesized in the small intestine and after entry into the ER is incorporated into chylomicrons when lipids are abundant, for example, after a triacylglycerol‐ and cholesterol‐rich meal.…”

“…Both forms of ApoB contain multiple aggregation‐prone β‐sheets and shorter α‐helices, creating its amphipathic nature and allowing for cholesterol, triacylglycerol, and fatty acid binding and transport in the blood. Shorter forms of ApoB (e.g., ApoB29) have also been detected in humans, and although these individuals suffer from hypolipidemia because the protein binds lower levels of lipids/cholesterol, ApoB29 still undergoes proper regulation in the secretory pathway and has been expressed and examined in yeast . Second, we fused the second nucleotide‐binding domain (NBD2) from the cystic fibrosis transmembrane conductance regulator (CFTR) to a transmembrane helical hairpin to tether this domain to the ER membrane.…”

“…Among these mutations is a truncation in NBD2 (W1282X), which results in a poorly expressed yet potentially correctable mutant protein, as well as a point mutation (N1303K) that appears to stabilize the protein . Based on the fact that the W1282X truncation resides in a central core of the NBD2—and because of the highly hydrophobic nature of ApoB, which is targeted for ERAD under lipid‐poor conditions—we hypothesized that these substrates would be aggregation prone and thus Hsp104‐dependent ERAD substrates in yeast. As outlined below, this hypothesis was correct, lending support to the view that ERAD substrates can also aggregate in human cells and that an Hsp104‐like activity must exist in the cytosol to ensure clearance of these toxic species.…”

Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease

“…Once in the Golgi they acquire apoA1 and apoE apolipoproteins and get further lapidated [ 41 ]. Finally, mature VLDL particles are secreted into the bloodstream and transport lipids to peripheral tissues [ 42 ].…”