ABCG5/ABCG8-independent mechanisms fail to maintain sterol balance in mice fed a high-cholesterol diet

The ABCG5/ABCG8 (G5G8) sterol transporter opposes the accumulation of dietary xenosterols but is also the primary mediator of biliary cholesterol secretion. In humans and in mouse models of disrupted biliary cholesterol secretion, fecal neutral sterols (FNSs) remain constant, indicating the presence of an alternate pathway for cholesterol excretion. Transintestinal cholesterol elimination or excretion (TICE) is thought to compensate for biliary disruptions and G5G8 insufficiency. We sought to measure the compensatory increase in intestinal cholesterol secretion and provide mechanistic insight for how TICE maintains sterol balance in the absence of hepatic G5G8. Differences were not observed in FNSs between control, acute, and chronic liver-specific G5G8-deficient mice (G5G8^LKO). Cholesterol content did not differ at any point along the intestinal tract between genotypes. We also observed no change in the expression of apical or basolateral sterol transporters in the proximal small intestine. We then measured biliary and intestinal cholesterol secretion rates using cholesterol-free and cholesterol-enriched bile acid micelles as acceptors. While biliary cholesterol secretion was reduced, the intrinsic rate of intestinal cholesterol secretion did not differ between genotypes. G5G8^LKO and whole-body G5G8-deficient mice were challenged with a cholesterol-containing diet. While control mice upregulate FNS excretion, G5G8-independent mechanisms fail to maintain fecal sterol excretion and oppose the accumulation of cholesterol in liver and plasma. These studies indicate that while G5G8-independent mechanisms can mediate cholesterol excretion, TICE is not upregulated in response to a loss of hepatic G5G8 and is unable to compensate for hepatic or whole-body G5G8 deficiency in response to dietary cholesterol in mice.