Impact of Hepatic ABCA1 (ATP-Binding Cassette Transporter A1) Deletion on Reverse Cholesterol Transport A New Clue in Solving Complex HDL (High-Density Lipoprotein) Metabolism

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 39, No. 9Impact of Hepatic ABCA1 (ATP-Binding Cassette Transporter A1) Deletion on Reverse Cholesterol Transport A New Clue in Solving Complex HDL (High-Density Lipoprotein) Metabolism Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBImpact of Hepatic ABCA1 (ATP-Binding Cassette Transporter A1) Deletion on Reverse Cholesterol Transport A New Clue in Solving Complex HDL (High-Density Lipoprotein) Metabolism Makoto Sasaki, Tomohiro Komatsu and Katsunori Ikewaki Makoto SasakiMakoto Sasaki From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (M.S., T.K., K.I.) Search for more papers by this author , Tomohiro KomatsuTomohiro Komatsu From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (M.S., T.K., K.I.) Research Institute for Physical Activity, Fukuoka University, Japan (T.K.). Search for more papers by this author and Katsunori IkewakiKatsunori Ikewaki Correspondence to: Katsunori Ikewaki, MD, PhD, Division of Anti-aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Japan 359–8513. Email E-mail Address: [email protected] From the Division of Anti-aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan (M.S., T.K., K.I.) Search for more papers by this author Originally published21 Aug 2019https://doi.org/10.1161/ATVBAHA.119.313016Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39:1699–1701This article is a commentary on the followingTargeted Deletion of Hepatocyte Abca1 Increases Plasma HDL (High-Density Lipoprotein) Reverse Cholesterol Transport via the LDL (Low-Density Lipoprotein) ReceptorRecent studies have shown that HDL (high-density lipoprotein) functions play pivotal roles in preventing arteriosclerotic diseases.1 Reverse cholesterol transport (RCT), a major HDL function, removes excess cholesterol from peripheral tissues and transports it to the liver for excretion in the bile, then into the feces.2,3See accompanying article on page 1747ABCA1 (ATP-binding cassette transporter A1) is an important protein associated with RCT.4,5 ABCA1 is essential for the biogenesis of nascent HDL particles in the liver5 and for the prevention of excess cholesterol accumulation by promoting cholesterol efflux from peripheral tissues to lipid poor apo AI.6To investigate the role of hepatic ABCA1 in RCT and development of atherosclerosis, several hepatic ABCA1 studies have been performed.7–11 Bi et al recently showed that hepatocyte-specific ABCA1 knockout (HSKO) in LDLrKO (LDL receptor knockout) mice fed an atherogenic diet surprisingly maintained in vivo RCT compared with LDLrKO, despite significantly lower HDL concentrations (50%). Interestingly, the HSKO in LDL receptor knockout mice had significantly lower aortic root intimal areas (20%–40%), indicating that in vivo RCT preserved by liver-specific ABCA1 knockout favorably affected atherosclerosis.10 Furthermore, Yamamoto et al11 showed that probucol significantly reduced HDL-C levels, by 80%, but increased HDL RCT into feces. These results suggest that expression of hepatic ABCA1, a key protein for the biogenesis of nascent HDL particles, is not always associated with maintaining in vivo RCT.However, these studies fail to adequately clarify the role of hepatocyte ABCA1 in plasma HDL RCT and recycling of hepatic cholesterol into plasma. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Bashore et al12 showed that selective HDL-CE removal from plasma and feces cholesterol was increased in HSKO mice compared with control mice. Surprisingly, they further demonstrated that the increased uptake of HDL was mediated by hepatic LDLr expression and that specific hepatic deletion of ABCA1 reduced overall recycling of plasma HDL-C—taken up by liver, returned to the plasma circulation—and increased the portion of resecreted free cholesterol into VLDL (very-low–density lipoprotein) particles instead of HDL particles, thereby affecting the quantity and compartmentalization of resecreted hepatic free cholesterol (Figure).Download figureDownload PowerPointFigure. Schematic diagram summarizing HDL (high-density lipoprotein) reverse cholesterol transport metabolism under the presence or absence of hepatic ABCA1. Left, Wild type; right, hepatocyte-specific ABCA1 knockout. Broken circle in pink: detailed uptake mechanisms remain unknown. ABCA1 indicates ATP-binding cassette transporter A1; CE; cholesterol ester; FC, free cholesterol; LDLR, LDL receptor; SRB I, scavenger receptor class B type I; and VLDL, very-low–density lipoprotein.These findings greatly advance our understanding of the roles of hepatic ABCA1 in HDL metabolism. It is particularly noteworthy that, based on previous studies, HSKO directly reduced overall recycling of plasma HDL-C, although there was no direct in vivo evidence.Despite this great progress, questions about the influence of HSKO in HDL metabolism remain. First, it comes as a surprise that increased hepatic uptake of HDL-CE by LDLr was not because of increased LRLr expression in HSKO mice compared with control mice. Bashore et al speculate that there may be greater hepatocyte LDLr surface expression or faster endocytic recycling back to the plasma membrane in HSKO mice.12 However, Rinninger et al reported that hepatic expression of LDLr influenced HDL-CE uptake by the liver, but HDL did not interact directly with LDLr. They also demonstrated that the influence of LDLr expression on uptake of HDL-CE by the liver was not mediated by changes in membrane expression of SR-BI, CD36, or LRP1 (low-density lipoprotein receptor-related protein 1).13 These findings seem inconsistent with the authors’ concept. As mentioned later, in CETP (cholesteryl ester transfer protein)-expressing humans, HDL particle uptake by LDLr is less efficient than in mice. Therefore, further investigations are needed to clarify the roles of LDLr in HDL uptake by the liver.Second, although Bashore et al emphasized that hepatic-specific ABCA1 deletion increased HDL-to-feces RCT, they showed that macrophage-to-feces RCT was not changed. A possible reason for increased HDL-to-feces RCT failing to increase the whole RCT process is that a decrease in the cargo (HDL) carried because of lack of hepatic ABCA1 reduces the cholesterol efflux capacity of HDL from macrophages. However, in this regard, it cannot necessarily be said that liver-specific deletion of ABCA1 could be a novel therapeutic strategy for atherosclerosis.Finally, the findings of the current study using CETP lacking mice cannot be simply applied to CETP-expressing humans. As stated above, CETP facilitates CE re-distribution within HDL and between apoB-containing lipoproteins, thereby preventing formation of apoE-containing buoyant HDL, which is a good substrate for particle uptake by LDLr. Therefore, it would be interesting to perform HSKO studies using CETP overexpressing mice or hamsters.In conclusion, the findings of Bashore et al greatly aid our understanding of the complex roles of hepatic ABCA1 in HDL metabolism, though they raise new questions. Therefore, we will need to wait for future studies to clarify the scheme of hepatic ABCA1 and reverse cholesterol transport, and ultimately its relationship with atherosclerosis.DisclosuresNone.FootnotesCorrespondence to: Katsunori Ikewaki, MD, PhD, Division of Anti-aging and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Japan 359–8513. Email [email protected]comReferences1. Rader DJ. New therapeutic approaches to the treatment of syslipidemia.Cell Metab. 2016; 23:405–412. doi: 10.1016/j.cmet.2016.01.005CrossrefMedlineGoogle Scholar2. 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Pharmacologic suppression of hepatic ATP-binding cassette transporter 1 activity in mice reduces high-density lipoprotein cholesterol levels but promotes reverse cholesterol transport.Circulation. 2011; 124:1382–1390. doi: 10.1161/CIRCULATIONAHA.110.009704LinkGoogle Scholar12. Bashore AC, Liu M, Key C.-C.C, Boudyguina E, Wang X, Carroll CM, Sawyer JK, Mullick AE, Lee RG, Macauley SL, et al. Targeted deletion of hepatocyte Abca1 increases plasma HDL (high-density lipoprotein) reverse cholesterol transport via the LDL (low-density lipoprotein) receptor.Arterioscler Thromb Vasc Biol. 2019; 39:1747–1761. doi: 10.1161/ATVBAHA.119.312382LinkGoogle Scholar13. Rinninger F, Heine M, Singaraja R, Hayden M, Brundert M, Ramakrishnan R, Heeren J. High density lipoprotein metabolism in low density lipoprotein receptor-deficient mice.J Lipid Res. 2014; 55:1914–1924. doi: 10.1194/jlr.M048819CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Xie Q, Peng J, Guo Y and Li F (2021) MicroRNA-33-5p inhibits cholesterol efflux in vascular endothelial cells by regulating citrate synthase and ATP-binding cassette transporter A1, BMC Cardiovascular Disorders, 10.1186/s12872-021-02228-7, 21:1, Online publication date: 1-Dec-2021. Yoon H, Lee Y, Park H, Kang H, Ji Y and Holzapfel W (2021) Lactobacillus johnsonii BFE6154 Ameliorates Diet-Induced Hypercholesterolemia, Probiotics and Antimicrobial Proteins, 10.1007/s12602-021-09859-4 Pathak G, Wendt F, De Lillo A, Nunez Y, Goswami A, De Angelis F, Fuciarelli M, Kranzler H, Gelernter J and Polimanti R (2021) Epigenomic Profiles of African-American Transthyretin Val122Ile Carriers Reveals Putatively Dysregulated Amyloid Mechanisms, Circulation: Genomic and Precision Medicine, 14:1, Online publication date: 1-Feb-2021.Zhou Y, Huang C, Hu Y, Xu Q and Hu X (2020) Lymphatics in Cardiovascular Disease, Arteriosclerosis, Thrombosis, and Vascular Biology, 40:11, (e275-e283), Online publication date: 1-Nov-2020.Related articlesTargeted Deletion of Hepatocyte Abca1 Increases Plasma HDL (High-Density Lipoprotein) Reverse Cholesterol Transport via the LDL (Low-Density Lipoprotein) ReceptorAlexander C. Bashore, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39:1747-1761 September 2019Vol 39, Issue 9 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.119.313016PMID: 31433697 Originally publishedAugust 21, 2019 KeywordsEditorialfecesbileliverhepatocytesPDF download Advertisement