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Recent Advances in the Critical Role of the Sterol Efflux Transporters ABCG5/G8 in Health and Disease

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Lipid Transfer in Lipoprotein Metabolism and Cardiovascular Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1276))

Abstract

Cardiovascular disease is characterized by lipid accumulation, inflammatory response, cell death, and fibrosis in the arterial wall and is the leading cause of morbidity and mortality worldwide. Cholesterol gallstone disease is caused by complex genetic and environmental factors and is one of the most prevalent and costly digestive diseases in the USA and Europe. Although sitosterolemia is a rare inherited lipid storage disease, its genetic studies led to identification of the sterol efflux transporters ABCG5/G8 that are located on chromosome 2p21 in humans and chromosome 17 in mice. Human and animal studies have clearly demonstrated that ABCG5/G8 play a critical role in regulating hepatic secretion and intestinal absorption of cholesterol and plant sterols. Sitosterolemia is caused by a mutation in either the ABCG5 or the ABCG8 gene alone, but not in both simultaneously. Polymorphisms in the ABCG5/G8 genes are associated with abnormal plasma cholesterol metabolism and may play a key role in the genetic determination of plasma cholesterol concentrations. Moreover, ABCG5/G8 is a new gallstone gene, LITH9. Gallstone-associated variants in ABCG5/G8 are involved in the pathogenesis of cholesterol gallstones in European, Asian, and South American populations. In this chapter, we summarize the latest advances in the critical role of the sterol efflux transporters ABCG5/G8 in regulating hepatic secretion of biliary cholesterol, intestinal absorption of cholesterol and plant sterols, the classical reverse cholesterol transport, and the newly established transintestinal cholesterol excretion, as well as in the pathogenesis and pathophysiology of ABCG5/G8-related metabolic diseases such as sitosterolemia, cardiovascular disease, and cholesterol gallstone disease.

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Abbreviations

ABC:

ATP-binding cassette (transporter)

ACAT2:

Acyl-CoA: cholesterol acyltransferase isoform 2

APO:

Apolipoprotein

CSI:

Cholesterol saturation index

CYP7A1:

Cholesterol 7α-hydroxylase

CYP27A1:

Sterol 27-hydroxylase

FABPpm:

Plasma membrane-associated fatty acid-binding protein

FATP4:

Fatty acid transport protein 4

FXR:

Farnesoid X receptor

HDL:

High-density lipoprotein

HMGCR:

3-Hydroxy-3-methylglutaryl coenzyme A reductase

LDL:

Low-density lipoprotein

LXR:

Liver X receptor

MTTP:

Microsomal triglyceride transfer protein

NPC1L1:

Niemann-Pick C1 like 1 (protein)

PPAR-δ:

Peroxisome proliferator-activated receptor-delta

QTL:

Quantitative trait locus

SR-BI:

Scavenger receptor class B type I

TICE:

Transintestinal cholesterol excretion

VLDL:

Very-low-density lipoprotein

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Acknowledgments

This work was supported in part by research grants DK101793, DK106249, DK114516, and AA025737 (to DQ-HW), as well as P30 DK041296 (to Marion Bessin Liver Research Center), all from the National Institutes of Health (US Public Health Service). This chapter was modified from the paper published by our group in Annals of Hepatology (Helen H. Wang, Gabriella Garruti, Min Liu, Piero Portincasa, David Q.-H. Wang. 2017; 16 (Suppl. 1): s28–s43). The related contents are re-used with the permission.

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There is no conflict of interest to disclose for all authors.

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Authors and Affiliations

  1. Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Helen H. Wang & David Q.-H. Wang

  2. Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Min Liu

  3. Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, Bari, Italy

    Piero Portincasa

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  1. Helen H. Wang
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  2. Min Liu
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  3. Piero Portincasa
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  4. David Q.-H. Wang
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Correspondence to David Q.-H. Wang .

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  1. Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

    Xian-Cheng Jiang

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Wang, H.H., Liu, M., Portincasa, P., Wang, D.QH. (2020). Recent Advances in the Critical Role of the Sterol Efflux Transporters ABCG5/G8 in Health and Disease. In: Jiang, XC. (eds) Lipid Transfer in Lipoprotein Metabolism and Cardiovascular Disease. Advances in Experimental Medicine and Biology, vol 1276. Springer, Singapore. https://doi.org/10.1007/978-981-15-6082-8_8

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