The ABCG5 ABCG8 Sterol Transporter Opposes the Development of Fatty Liver Disease and Loss of Glycemic Control Independently of Phytosterol Accumulation

Abstract

Background: G5G8 promotes elimination of cholesterol. Results: The absence of G5G8 accelerates the loss of glycemic control and exacerbates the development of steatosis. Conclusion: G5G8 mitigates the impact of a high fat diet on hepatic lipid accumulation and glucose intolerance. Significance: Increased G5G8 in insulin resistance may be an adaptive mechanism that opposes steatosis but increases the risk of cholesterol gallstones.

Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol

“…77,78) 3.2. ABCG5/G8 and Gallstone Although ABCG5/G8 KO mice showed increased liver weight, hepatic lipids accumulation, higher plasma ALT, and increased fasting glucose levels compared with WT mice, 79) there is little information on liver histology and glucose metabolism in patients with sitosterolemia except for one patient with chronic active hepatitis and signs of cirrhosis. 80) Meanwhile, associations of cholesterol gallstone disease with mutations of ABCG5/G8 have been revealed in humans by a number of gene mutation analyses and GWAS.…”

The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination

“…Urso capsules, USP (NDC 42806-503-01) were purchased from Epic Pharma LLC, and Zetia (EZ) tablets (NDC 66582-414-54) from Merck and Co. Inc. Urethane, bromodeoxyuridine (BrdU), and the silylation reagent N , O -bis (trimethylsilyl) trifl uoroacetamide were purchased from SigmaAldrich. The chicken anti-G5 polyclonal antibody and the monoclonal antibody directed against G8 were previously reported ( 6,14 ). The ␤ -actin antibody was purchased from Sigma.…”

“…The ␤ -actin antibody was purchased from Sigma. Anti-ABCA1, [26, 26, 26, 27, 27, 27-2 H 6 ]cholesterol and [5,6,22, H 4 ]sitostanol were generous gifts from Ryan Temel (University of Kentucky) ( 15 ). The anti-CD3 monoclonal antibody (clone 145-2C11) was purifi ed over protein G beads (Amersham Pharmacia Biotech, Piscataway, NJ).…”

“…Custom formulated pellet (D10040301) and powdered (D10040301M) PSF diets were purchased from Research Diets Inc. Macronutrient composition and sterol content were previously described ( 6 ). There was no added cholesterol in the diet.…”

“…Mice homozygous for the Abcg5 and Abcg8 mutant alleles (KO) and their WT littermates were obtained from heterozygous, trio matings as previously described ( 6 ). Mice were housed in individually ventilated cages in a temperature-controlled room with a 14:10 light:dark cycle and provided with enrichment in the form of acrylic huts, wood chew sticks, and nesting material.…”