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ABCG5 and ABCG8 Are Involved in Vitamin K Transport.

ABSTRACT: ATP-binding cassette protein G5 (ABCG5)/ABCG8 heterodimer exports cholesterol from cells, while Niemann-Pick C1-like 1 (NPC1L1) imports cholesterol and vitamin K. We examined whether ABCG5/ABCG8 transports vitamin K similar to NPC1L1. Since high concentrations of vitamin K₃ show cytotoxicity, the cytoprotective effects of ABCG5/ABCG8 were examined. BHK cells expressing ABCG5/ABCG8 were more resistant to vitamin K₃ cytotoxicity than control cells, suggesting that ABCG5/ABCG8 transports vitamin K₃ out of cells. The addition of vitamin K₁ reversed the effects of ABCG5/ABCG8, suggesting that vitamin K₁ competitively inhibits the transport of vitamin K₃. To examine the transport of vitamin K₁ by ABCG5/ABCG8, vitamin K₁ levels in the medium and cells were measured. Vitamin K₁ levels in cells expressing ABCG5/ABCG8 were lower than those in control cells, while vitamin K₁ efflux increased in cells expressing ABCG5/ABCG8. Furthermore, the biliary vitamin K₁ concentration in Abcg5/Abcg8-deficient mice was lower than that in wild-type mice, although serum vitamin K₁ levels were not affected by the presence of Abcg5/Abcg8. These findings suggest that ABCG5 and ABCG8 are involved in the transport of sterols and vitamin K. ABCG5/ABCG8 and NPC1L1 might play important roles in the regulation of vitamin K absorption and excretion.

SUBMITTER: Matsuo M

PROVIDER: S-EPMC9966996 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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ABCG5 and ABCG8 Are Involved in Vitamin K Transport.

Matsuo Michinori M Ogata Yutaka Y Yamanashi Yoshihide Y Takada Tappei T

Nutrients 20230216 4

ATP-binding cassette protein G5 (ABCG5)/ABCG8 heterodimer exports cholesterol from cells, while Niemann-Pick C1-like 1 (NPC1L1) imports cholesterol and vitamin K. We examined whether ABCG5/ABCG8 transports vitamin K similar to NPC1L1. Since high concentrations of vitamin K<sub>3</sub> show cytotoxicity, the cytoprotective effects of ABCG5/ABCG8 were examined. BHK cells expressing ABCG5/ABCG8 were more resistant to vitamin K<sub>3</sub> cytotoxicity than control cells, suggesting that ABCG5/ABCG8 ...[more]

PMID: 36839356

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Project description:BackgroundThe molecular mechanisms that regulate the entry of dietary sterols into the body and their removal via hepatobiliary secretion are now beginning to be defined. These processes are specifically disrupted in the rare autosomal recessive disease, Sitosterolemia (MIM 210250). Mutations in either, but not both, of two genes ABCG5 or ABCG8, comprising the STSL locus, are now known to cause this disease and their protein products are proposed to function as heterodimers. Under normal circumstances cholesterol, but not non-cholesterol sterols, is preferentially absorbed from the diet. Additionally, any small amounts of non-cholesterol sterols that are absorbed are rapidly taken up by the liver and preferentially excreted into bile. Based upon the defects in sitosterolemia, ABCG5 and ABCG8 serve specifically to exclude non-cholesterol sterol entry at the intestinal level and are involved in sterol excretion at the hepatobiliary level.MethodsHere we report the biochemical and immuno-localization of ABCG5 and ABCG8 in human liver, gallbladder and intestine using cell fractionation and immunohistochemical analyses.ResultsWe raised peptide antibodies against ABCG5 and ABCG8 proteins. Using human liver samples, cell fractionation studies showed both proteins are found in membrane fractions, but they did not co-localize with caveolin-rafts, ER, Golgi or mitochondrial markers. Although their distribution in the sub-fractions was similar, they were not completely contiguous. Immunohistochemical analyses showed that while both proteins were readily detectable in the liver, ABCG5 was found predominately lining canalicular membranes, whereas ABCG8 was found in association with bile duct epithelia. At the cellular level, ABCG5 appeared to be apically expressed, whereas ABCG8 had a more diffuse expression pattern. Both ABCG5 and ABCG8 appeared to localize apically as shown by co-localization with MRP2. The distribution patterns of ABCG5 and ABCG8 in the gallbladder were very similar to each other. In the small intestine both ABCG5 and ABCG8 appear to line the brush border. However, at the level of the enterocyte, the cellular distribution patterns of ABCG5 and ABCG8 differed, such that ABCG5 was more diffuse, but ABCG8 was principally apical. Using standard deglycosylation methods, ABCG5 and ABCG8 do not appear to be glycosylated, suggesting a difference between human and mouse proteins.ConclusionWe report the distribution patterns of ABCG5 and ABCG8 in human tissues. Cell fractionation studies showed that both proteins co-fractionated in general, but could also be found independent of each other. As predicted, they are expressed apically in both intestine and liver, although their intracellular expression patterns are not completely congruent. These studies support the concept of heterodimerization of ABCG5 and ABCG8, but also support the notion that these proteins may have an independent function.

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ABCG5 and ABCG8 Are Involved in Vitamin K Transport.

Publications

ABCG5 and ABCG8 Are Involved in Vitamin K Transport.

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