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      Targeted Deletion of Hepatocyte Abca1 Increases Plasma HDL (High-Density Lipoprotein) Reverse Cholesterol Transport via the LDL (Low-Density Lipoprotein) Receptor

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          Abstract

          The role of hepatocyte ATP binding cassette transporter A1 (Abca1) in trafficking hepatic free cholesterol (FC) into plasma versus bile for reverse cholesterol transport (RCT) is poorly understood. We hypothesized that hepatocyte Abca1 recycles plasma HDL cholesterol (HDL-C) taken up by the liver back into plasma, maintaining the plasma HDL-C pool and decreasing HDL-mediated RCT into feces. Chow-fed hepatocyte-specific Abca1 knockout (HSKO) and control mice were injected with human HDL radiolabeled with 125 I-tyramine cellobiose ( 125 I-TC;protein) and 3 H-cholesteryl oleate ( 3 H-CO). 125 I-TC and 3 H-CO plasma decay, plasma HDL 3 H-CO selective clearance (i.e., 3 H- 125 I fractional catabolic rate), liver radiolabel uptake, and fecal 3 H-sterol were significantly greater in HSKO versus control mice, supporting increased plasma HDL RCT. Twenty-four hours after 3 H-CO-HDL injection, HSKO mice had reduced total hepatic 3 H-FC (i.e., 3 H-CO hydrolyzed to 3 H-FC in liver) resecretion into plasma, demonstrating Abca1 recycled HDL-derived hepatic 3 H-FC back into plasma. Despite similar liver LDL receptor (LDLr) expression between genotypes, HSKO mice treated with LDLr-targeting versus control antisense oligonucleotide had slower plasma 3 H-CO-HDL decay, reduced selective 3 H-CO clearance, and decreased fecal 3 H-sterol excretion that were indistinguishable from control mice. Increased RCT in HSKO mice was selective for 3 H-CO-HDL, since macrophage RCT was similar between genotypes. Hepatocyte Abca1 deletion unmasks a novel and selective FC trafficking pathway that requires LDLr expression, accelerating plasma HDL-selective CE uptake by the liver and promoting HDL RCT into feces, consequently reducing HDL-derived hepatic FC recycling into plasma.

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          Most cited references36

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          The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.

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            Identification of Scavenger Receptor SR-BI as a High Density Lipoprotein Receptor

            High density lipoprotein (HDL) and low density lipoprotein (LDL) are cholesterol transport particles whose plasma concentrations are directly (LDL) and inversely (HDL) correlated with risk for atherosclerosis. LDL catabolism involves cellular uptake and degradation of the entire particle by a well-characterized receptor. HDL, in contrast, selectively delivers its cholesterol, but not protein, to cells by unknown receptors. Here it is shown that the class B scavenger receptor SR-BI is an HDL receptor. SR-BI binds HDL with high affinity, is expressed primarily in liver and nonplacental steroidogenic tissues, and mediates selective cholesterol uptake by a mechanism distinct from the classic LDL receptor pathway.
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              Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.

              PCSK9 encodes proprotein convertase subtilisin/kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR) in mice. Here, we show that livers of knockout mice lacking PCSK9 manifest increased LDLR protein but not mRNA. Increased LDLR protein led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg/dl in Pcsk9(-/-) mice versus 96 mg/dl in WT mice). Statins, a class of drugs that inhibit cholesterol synthesis, increase expression of sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor that activates both the Ldlr and Pcsk9 genes. Statin administration to Pcsk9(-/-) mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. These data demonstrate that PCSK9 regulates the amount of LDLR protein in liver and suggest that inhibitors of PCSK9 may act synergistically with statins to enhance LDLRs and reduce plasma cholesterol.
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                Author and article information

                Journal
                Arteriosclerosis, Thrombosis, and Vascular Biology
                ATVB
                Ovid Technologies (Wolters Kluwer Health)
                1079-5642
                1524-4636
                September 2019
                September 2019
                : 39
                : 9
                : 1747-1761
                Affiliations
                [1 ]From the Department of Internal Medicine, Section of Molecular Medicine (A.C.B., M.L., C-C.C.K., E.B., X.W., J.K.S., J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC
                [2 ]Department of Internal Medicine, Section on Gerontology and Geriatric Medicine (C.M.C., S.L.M.), Wake Forest School of Medicine, Winston-Salem, NC
                [3 ]Cardiovascular, Renal and Metabolic Group, Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, CA (A.E.M., R.G.L.).
                Article
                10.1161/ATVBAHA.119.312382
                6703909
                31167565
                2745a3c0-dea1-4a09-99c3-e23718482a83
                © 2019
                History

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