The ABCG5 ABCG8 sterol transporter and phytosterols: implications for cardiometabolic disease

Abstract

Purpose of review: This review summarizes recent developments in the activity, regulation, and physiology of the ABCG5 ABCG8 (G5G8) transporter and the use of its xenobiotic substrates, phytosterols, as cholesterol lowering agents in the treatment of cardiovascular disease. Recent progress has significant implications for the role of G5G8 and its substrates in complications associated with features of the metabolic syndrome.

Recent findings: Recent reports expand the clinical presentation of sitosterolemia to include platelet and adrenal dysfunction. The G5G8 sterol transporter is critical to hepatobiliary excretion of cholesterol under nonpathological conditions and has been linked to the cholesterol gallstone susceptibility. Finally, the cardiovascular benefits of cholesterol lowering through the use of phytosterol supplements were offset by vascular dysfunction, suggesting that alternative strategies to reduced cholesterol absorption offer greater benefit.

Summary: Insulin resistance elevates G5G8 and increases susceptibility to cholesterol gallstones. However, this transporter is critical for the exclusion of phytosterols from the absorptive pathways in the intestine. Challenging the limits of this protective mechanism through phytosterol supplementation diminishes the cardioprotective benefits of cholesterol lowering in mouse models of cardiovascular disease.

Figure 1. Regulatory elements within the ABCG5 ABCG8 intergenic promoter

ABCG5 and ABCG8 are located on 2p21, are separated by 374 base pairs, and are encoded on opposite strands of the DNA. Numbers between the strands represent base pairs from the G8 transcriptional start site. The locations of the regulatory elements within the intergenic promoter are indicated by arrows. LXR and thyroid hormone also regulate G5 and G8 mRNA, but regulatory elements for these have not been identified. FOXO, forkhead box O1A; HNF, hepatocyte nuclear factor.

Figure 2. Relationships among obesity, insulin resistance, endoplasmic reticulum stress, and leptin on the abundance of G5G8 and cholethiasis

Solid lines with arrows indicate positive regulation. Dashed lines with diamonds indicate negative regulation. Insulin resistance increase G5G8 expression via disinhibition of FOXO1. Despite obesity and insulin resistance, G5G8 is reduced in leptin-deficient mice. The mechanism by which leptin increases G5G8 is not known. ER, endoplasmic reticulum; FOXO1, forkhead box O1A.