ABCA1 and ABCG1 as potential therapeutic targets for the prevention of atherosclerosis.

Prevention of atherosclerosis is important because it is a risk factor for cardiovascular diseases globally. One of the causes of atherosclerosis is accumulation of cholesterol and triglycerides in peripheral cells. ATP-binding cassette protein A1 (ABCA1) and G1 (ABCG1) are important in eliminating excess cholesterol from cells including macrophages and forming high-density lipoprotein, which contributes to the prevention and regression of atherosclerosis. Enhanced cholesterol efflux activities of ABCA1 and ABCG1 are expected to prevent the progression of atherosclerosis. ABCA1 and ABCG1 are induced by the LXR/RXR pathway and regulated transcriptionally, post-transcriptionally, and post-translationally. Their mRNAs are destabilized by microRNAs and their cellular localization and degradation are regulated by other proteins and phosphorylation. Furthermore, ABCA1 and ABCG1 suppress the inflammatory responses of macrophages. These proteins are effective targets because their increased activities can suppress cholesterol accumulation and inflammation in macrophages. Moreover, ABCA1 and ABCG1 prevent amyloid ß accumulation; therefore, their increased activity may prevent Alzheimer's disease. Because ABCA1 and ABCG1 are affected by transcriptional, post-transcriptional, and post-translational regulation, the regulatory factors involved could also serve as therapeutic targets. This review highlights that ABCA1 and ABCG1 could be potential therapeutic targets for preventing atherosclerosis by regulating their expression, degradation, and localization.

Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect.

BACKGROUND: Adipogenesis, the process whereby preadipocytes differentiate into mature adipocytes, is crucial for maintaining metabolic homeostasis. Cholesterol-lowering statins increase type 2 diabetes (T2D) risk possibly by affecting adipogenesis and insulin resistance but the (epi)genetic mechanisms involved are unknown. Here, we characterised the effects of statin treatment on adipocyte differentiation using in vitro human preadipocyte cell model to identify putative effective genes. RESULTS: Statin treatment during adipocyte differentiation caused a reduction in key genes involved in adipogenesis, such as ADIPOQ, GLUT4 and ABCG1. Using Illumina's Infinium '850K' Methylation EPIC array, we found a significant hypomethylation of cg14566882, located in the promoter of the histone deacetylase 9 (HDAC9) gene, in response to two types of statins (atorvastatin and mevastatin), which correlates with an increased HDAC9 mRNA expression. We confirmed that HDAC9 is a transcriptional repressor of the cholesterol efflux ABCG1 gene expression, which is epigenetically modified in obesity and prediabetic states. Thus, we assessed the putative impact of ABCG1 knockdown in mimicking the effect of statin in adipogenesis. ABCG1 KD reduced the expression of key genes involved in adipocyte differentiation and decreased insulin signalling and glucose uptake. In human blood cells from two cohorts, ABCG1 expression was impaired in response to statins, confirming that ABCG1 is targeted in vivo by these drugs. CONCLUSIONS: We identified an epigenetic link between adipogenesis and adipose tissue insulin resistance in the context of T2D risk associated with statin use, which has important implications as HDAC9 and ABCG1 are considered potential therapeutic targets for obesity and metabolic diseases.

High-Density Lipoprotein Function Is Reduced in Patients Affected by Genetic or Idiopathic Hypogonadism.

CONTEXT: Low testosterone levels are associated with an increased incidence of cardiovascular (CV) events, but the underlying biochemical mechanisms are not fully understood. The clinical condition of hypogonadism offers a unique model to unravel the possible role of lipoprotein-associated abnormalities in CV risk. In particular, the assessment of the functional capacities of high-density lipoproteins (HDLs) may provide insights besides traditional risk factors. DESIGN: To determine whether reduced testosterone levels correlate with lipoprotein function, HDL cholesterol (HDL-C) efflux capacity (CEC) and serum cholesterol loading capacity (CLC). PARTICIPANTS: Genetic and idiopathic hypogonadal patients (n = 20) and control subjects (n = 17). RESULTS: Primary and secondary hypogonadal patients presented with lower HDL ATP-binding cassette transporter A1 (ABCA1)-, ATP-binding cassette transporter G1 (ABCG1)-, and aqueous diffusion-mediated CEC (-19.6%, -40.9%, and -12.9%, respectively), with a 16.2% decrement of total CEC. In the whole series, positive correlations between testosterone levels and both total HDL CEC (r2 = 0.359, P = 0.0001) and ABCG1 HDL CEC (r2 = 0.367, P = 0.0001) were observed. Conversely, serum CLC was markedly raised (+43%) in hypogonadals, increased, to a higher extent, in primary vs secondary hypogonadism (18.45 ± 2.78 vs 15.15 ± 2.10 µg cholesterol/mg protein) and inversely correlated with testosterone levels (r2 = 0.270, P = 0.001). HDL-C concentrations did not correlate with either testosterone levels, HDL CEC (total, ABCG1, and ABCA1) or serum CLC. CONCLUSIONS: In hypogonadal patients, proatherogenic lipoprotein-associated changes are associated with lower cholesterol efflux and increased influx, thus offering an explanation for a potentially increased CV risk.

The ATP binding cassette transporter, ABCG1, localizes to cortical actin filaments.

The ATP-binding cassette sub-family G member 1 (ABCG1) exports cellular cholesterol to high-density lipoproteins (HDL). However, a number of recent studies have suggested ABCG1 is predominantly localised to intracellular membranes. In this study, we found that ABCG1 was organized into two distinct cellular pools: one at the plasma membrane and the other associated with the endoplasmic reticulum (ER). The plasma membrane fraction was organized into filamentous structures that were associated with cortical actin filaments. Inhibition of actin polymerization resulted in complete disruption of ABCG1 filaments. Cholesterol loading of the cells increased the formation of the filamentous ABCG1, the proximity of filamentous ABCG1 to actin filaments and the diffusion rate of membrane associated ABCG1. Our findings suggest that the actin cytoskeleton plays a critical role in the plasma membrane localization of ABCG1.