Thematic Review Series: Lipid Transfer Proteins ABCG5 and ABCG8: more than a defense against xenosterols

Abstract

The elucidation of the molecular basis of the rare disease, sitosterolemia, has revolutionized our mechanistic understanding of how dietary sterols are excreted and how cholesterol is eliminated from the body. Two proteins, ABCG5 and ABCG8, encoded by the sitosterolemia locus, work as obligate dimers to pump sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body sterol trafficking, by eliminating sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body. The sitosterolemia locus has been genetically associated with lipid levels and downstream atherosclerotic disease, as well as formation of gallstones and the risk of gallbladder cancer. While polymorphic variants raise or lower the risks of these phenotypes, loss of function of this locus leads to more dramatic phenotypes, such as premature atherosclerosis, platelet dysfunction, and thrombocytopenia, and, perhaps, increased endocrine disruption and liver dysfunction. Whether small amounts of xenosterol exposure over a lifetime cause pathology in normal humans with polymorphic variants at the sitosterolemia locus remains largely unexplored. The purpose of this review will be to summarize the current state of knowledge, but also highlight key conceptual and mechanistic issues that remain to be explored.

Structural snapshot of the cholesterol-transport ATP-binding cassette proteins

“…a Summarized based on the crystal structure of human ABCG5/G8 (Lee et al 2016) and a review by Patel et al (2018).…”

“…Absence of ABCG5/G8 is associated with hepatic steatosis, i.e., lipid accumulation in the liver, and its inhibition is involved in the development of non-alcohol fatty liver disease (NAFLD) in the pathogenesis of obesity (Miettinen et al 2006;van Rooyen et al 2011). In addition, ABCG5/G8 is believed to participate in trans-intestinal cholesterol (or sterol) excretion(TICE or TISE) (van der Velde et al 2008;Patel et al 2018). Together, ABCG5/G8 is a promising drug target for treatment of hepatic and cholestatic disorders.…”

Plant Glycosides and Glycosidases: A Treasure-Trove for Therapeutics

“…This led to the industrial production of phytosterol enriched food products such as margarines and yogurts (AbuMweis and Jones, 2008;Amiot et al, 2011;Trautwein et al, 2018;Nakano et al, 2019). It is generally accepted that 1-3 g of a daily dose of phytosterols leads to a 10-15% decrease of total cholesterol levels and also decreases plasma LDL-cholesterol (Patel et al, 2018;Nakano et al, 2019).…”

“…ABCG5/ABCG8 excretes phytosterols and other xenosterols from cells, even better than cholesterol. Impaired ABCG5/ABCG8 leads to accumulation of phytosterols in the body causing macrothrombocytopenia, platelet dysfunction, liver disease, cholesterol accumulation with xanthoma formation and atherosclerosis (Silbernagel et al, 2013;Patel et al, 2018).…”

Genes Potentially Associated with Familial Hypercholesterolemia

“…ABCG5-ABCG8 is the main carrier of xenosterols and a transporter of excess cholesterol into the intestinal lumen from enterocytes and into bile from hepatocytes [68,69]. Moreover, it has been found that the ABCG5-ABCG8 complex lowers the absorption of cholesterol from the intestinal lumen [74,75].…”