Hepatic LDL receptor-related protein-1 deficiency alters mitochondrial dynamics through phosphatidylinositol 4,5-bisphosphate reduction

Abstract

The LDL receptor-related protein 1 (LRP1) is a multifunctional transmembrane protein with endocytosis and signal transduction functions. Previous studies have shown that hepatic LRP1 deficiency exacerbates diet-induced steatohepatitis and insulin resistance via mechanisms related to increased lysosome and mitochondria permeability and dysfunction. The current study examined the impact of LRP1 deficiency on mitochondrial function in the liver. Hepatocytes isolated from liver-specific LRP1 knockout (hLrp1−/−) mice showed reduced oxygen consumption compared with control mouse hepatocytes. The mitochondria in hLrp1−/− mouse livers have an abnormal morphology and their membranes contain significantly less anionic phospholipids, including lower levels of phosphatidylethanolamine and cardiolipin that increase mitochondrial fission and impair fusion. Additional studies showed that LRP1 complexes with phosphatidylinositol 4-phosphate 5-kinase like protein-1 (PIP5KL1) and phosphatidylinositol 4-phosphate 5-kinase-1β (PIP5K1β). The absence of LRP1 reduces the levels of both PIP5KL1 and PIP5K1β in the plasma membrane and also lowers phosphatidylinositol(4,5) bisphosphate (PI(4,5)P2) levels in hepatocytes. These data indicate that LRP1 recruits PIP5KL1 and PIP5K1β to the plasma membrane for PI(4,5)P2 biosynthesis. The lack of LRP1 reduces lipid kinase expression, leading to lower PI(4,5)P2 levels, thereby decreasing the availability of this lipid metabolite in the cardiolipin biosynthesis pathway to cause cardiolipin reduction and the impairment in mitochondria homeostasis. Taken together, the current study identifies another signaling mechanism by which LRP1 regulates cell functions: binding and recruitment of PIP5KL1 and PIP5K1β to the membrane for PI(4,5)P2 synthesis. In addition, it highlights the importance of this mechanism for maintaining the integrity and functions of intracellular organelles. The LDL receptor-related protein 1 (LRP1) is a multifunctional transmembrane protein with endocytosis and signal transduction functions. Previous studies have shown that hepatic LRP1 deficiency exacerbates diet-induced steatohepatitis and insulin resistance via mechanisms related to increased lysosome and mitochondria permeability and dysfunction. The current study examined the impact of LRP1 deficiency on mitochondrial function in the liver. Hepatocytes isolated from liver-specific LRP1 knockout (hLrp1−/−) mice showed reduced oxygen consumption compared with control mouse hepatocytes. The mitochondria in hLrp1−/− mouse livers have an abnormal morphology and their membranes contain significantly less anionic phospholipids, including lower levels of phosphatidylethanolamine and cardiolipin that increase mitochondrial fission and impair fusion. Additional studies showed that LRP1 complexes with phosphatidylinositol 4-phosphate 5-kinase like protein-1 (PIP5KL1) and phosphatidylinositol 4-phosphate 5-kinase-1β (PIP5K1β). The absence of LRP1 reduces the levels of both PIP5KL1 and PIP5K1β in the plasma membrane and also lowers phosphatidylinositol(4,5) bisphosphate (PI(4,5)P2) levels in hepatocytes. These data indicate that LRP1 recruits PIP5KL1 and PIP5K1β to the plasma membrane for PI(4,5)P2 biosynthesis. The lack of LRP1 reduces lipid kinase expression, leading to lower PI(4,5)P2 levels, thereby decreasing the availability of this lipid metabolite in the cardiolipin biosynthesis pathway to cause cardiolipin reduction and the impairment in mitochondria homeostasis. Taken together, the current study identifies another signaling mechanism by which LRP1 regulates cell functions: binding and recruitment of PIP5KL1 and PIP5K1β to the membrane for PI(4,5)P2 synthesis. In addition, it highlights the importance of this mechanism for maintaining the integrity and functions of intracellular organelles. Low-density lipoprotein receptor-related protein-1 (LRP1) is a type 1 transmembrane protein that serves endocytic and signaling functions through mechanisms that are cell type and context-dependent. For example, in macrophages, LRP1 is an endocytosis receptor for the uptake of aggregated LDL and efferocytosis of dead cells (1Llorente-Cortes V. Royo T. Juan-Babot O. Badimon L. Adipocyte differentiation-related protein is induced by LRP1-mediated aggregated LDL internalization in human vascular smooth muscle cells and macrophages.J. Lipid Res. 2007; 48: 2133-2140Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 2Yancey P.G. Blakemore J. Ding L. Fan D. Overton C.D. Zhang Y. Linton M.F. Fazio S. Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 787-795Crossref PubMed Scopus (96) Google Scholar). LRP1 in macrophages also serves important signal transduction functions including the activation of phosphatidylinositol 3-kinase to suppress toll-like receptor-induced inflammation (3Luo L. Wall A.A. Tong S.J. Hung Y. Xiao Z. Tarique A.A. Sly P.D. Fantino E. Marzolo M.P. Stow J.L. TLR crosstalk activates LRP1 to recruit Rab8a and PI3Kγ for suppression of inflammatory responses.Cell Rep. 2018; 24: 3033-3044Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar), as well as the activation of liver X receptor to increase ABCA1 expression to limit cholesterol accumulation (4Xian X. Ding Y. Diechmann M. Zhou L. Plattner F. Liu M. Parks J.S. Hammer R.E. Boucher P. Tsai S. Herz J. LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis.Elife. 2017; 6e29292Crossref PubMed Scopus (37) Google Scholar). The cardiometabolic benefits of macrophage LRP1 signaling are counterbalanced by its enhancement of Wnt signaling that leads to hepatic inflammation and insulin resistance (5Au D.T. Migliorini M. Strickland D.K. Muratoglu S.C. Macrophage LRP1 promotes diet-induced hepatic inflammation and metabolic dysfunction by modulating Wnt signaling.Mediators Inflamm. 2018; 2018: 7902841Crossref PubMed Scopus (5) Google Scholar). In smooth muscle cells, the role of LRP1 is primarily signal transduction regulation in limiting cellular response to platelet-derived growth factor and transforming growth factor-β (6Boucher P. Li W.-P. Matz R.L. Takayama Y. Auwerx J. Anderson R.G.W. Herz J. LRP1 functions as an atheroprotective integrator of TGFβ and PDGF signals in the vascular wall: Implications for marfan syndrome.PLoS One. 2007; 2: e448Crossref PubMed Scopus (85) Google Scholar). The lack of LRP1 in smooth muscle cells accelerates cholesterol-induced atherosclerosis as well as promotes injury-induced neointimal hyperplasia and vascular cardiomyopathy in a cholesterol-independent manner (7Boucher P. Gotthardt M. Li W.-P. Anderson R.G.W. Herz J. LRP: Role in vascular wall integrity and protection from atherosclerosis.Science. 2003; 300: 329-332Crossref PubMed Scopus (450) Google Scholar, 8Basford J.E. Moore Z.W.Q. Zhou L. Herz J. Hui D.Y. Smooth muscle LDL receptor-related protein-1 inactivation reduces vascular reactivity and promotes injury-induced neointima formation.Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1772-1778Crossref PubMed Scopus (32) Google Scholar, 9Basford J.E. Koch S. Anjak A. Singh V.P. Krause E.G. Robbins N. Weintraub N.L. Hui D.Y. Rubinstein J. Smooth muscle LDL receptor-related protein-1 deletion induces aortic insufficiency and promotes vascular cardiomyopathy in mice.PLoS One. 2013; 8e82026Crossref PubMed Scopus (8) Google Scholar). In preadipocytes, LRP1 is an integrator of adipogenic differentiation and fat storage signals through activation of Wnt signaling pathway (10Terrand J. Bruban V. Zhou L. Gong W. El Asmar Z. May P. Zurhove K. Hafner P. Philippe C. Woldt E. Matz R.L. Gracia C. Metzger D. Auwerx J. Herz J. et al.LRP1 controls intracellular cholesterol storage and fatty acid synthesis through modulation of Wnt signaling.J. Biol. Chem. 2009; 284: 381-388Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar), and the absence of LRP1 impairs adipocyte differentiation (11Masson O. Chavey C. Dray C. Meulle A. Daviaud D. Quilliot D. Muller C. Valet P. Liaudet-Coopman E. LRP1 receptor controls adipogenesis and is up-regulated in human and mouse obese adipose tissue.PLoS One. 2009; 4e7422Crossref PubMed Scopus (43) Google Scholar, 12Woldt E. Matz R.L. Terrand J. Mlih M. Gracia C. Foppolo S. Martin S. Bruban V. Ji J. Velot E. Herz J. Boucher P. Differential signaling by adaptor molecules LRP1 and ShcA regulates adipogenesis by the insulin-like growth factor-1 receptor.J. Biol. Chem. 2011; 286: 16775-16782Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). In mature adipocytes, LRP1 is required for basal lipolysis and insulin-induced translocation of glucose transporter-4 to the plasma membrane (10Terrand J. Bruban V. Zhou L. Gong W. El Asmar Z. May P. Zurhove K. Hafner P. Philippe C. Woldt E. Matz R.L. Gracia C. Metzger D. Auwerx J. Herz J. et al.LRP1 controls intracellular cholesterol storage and fatty acid synthesis through modulation of Wnt signaling.J. Biol. Chem. 2009; 284: 381-388Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 13Jedrychowski M.P. Gartner C.A. Gygi S.P. Zhou L. Herz J. Kandor K.V. Pilch P.F. Proteomic analysis of GLUT4 storage vesicles reveals LRP1 to be an important vesicle component and target of insulin signaling.J. Biol. Chem. 2010; 285: 104-114Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). The absence of LRP1 in mature adipocytes impairs lipid accumulation to limit diet-induced adiposity but also promotes inflammation in exacerbation of atherosclerosis (14Hofmann S.M. Zhou L. Perez-Tilve D. Greer T. Grant E. Wancata L. Thomas A. Pfluger P.T. Basford J.E. Gilham D. Herz J. Tschop M.H. Hui D.Y. Adipocyte LDL receptor-related protein-1 expression modulates postprandial lipid transport and glucose homeostasis in mice.J. Clin. Invest. 2007; 117: 3271-3282Crossref PubMed Scopus (123) Google Scholar, 15Konaniah E.S. Kuhel D.G. Basford J.E. Weintraub N.L. Hui D.Y. Deficiency of LRP1 in mature adipocytes promotes diet-induced inflammation and atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2017; 37: 1046-1049Crossref PubMed Scopus (15) Google Scholar). In the brain, LRP1 participates in the production and clearance of amyloid-β peptide and limits neuroinflammation (16Deane R. Wu Z. Sagare A. Davis J. Yan S.D. Hamm K. Xu F. Parisi M. LaRue B. Hu H.W. Spijkers P. Guo H. Song X. Lenting P.J. Van Nostrand W.E. et al.LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms.Neuron. 2004; 43: 333-344Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar, 17Van Gool B. Storck S.E. Reekmans S.M. Lechat B. Gordts P.L.S.M. Pradier l. Pietrzik C.U. Roebroek A.J.M. LRP1 has a predominant role in production over clearance of Ab in a mouse model of Alzheimer's disease.Mol. Neurobiol. 2019; 56: 7234-7245Crossref PubMed Scopus (31) Google Scholar, 18Yang L. Liu C.-C. Zheng H. Kanekiyo T. Atagi Y. Lia L. Wang D. N'songo A. Can D. Xu H. Chen X.-F. Bu G. LRP1 modulates the microglial immune response via regulation of JNK and NF-kB signaling pathways.J. Neuroinflammation. 2016; 13: 304Crossref PubMed Scopus (48) Google Scholar). LRP1 is also abundantly expressed in the liver, where it serves primarily an endocytic function and works in conjunction with LDL receptor for plasma clearance of apoE-containing lipoproteins (19Kowal R.C. Herz J. Goldstein J.L. Esser V. Brown M.S. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched S. A. PubMed Scopus Google Scholar). studies that LRP1 also a role in hepatocytes. The absence of LRP1 in reduces cell expression of leading to the of in the plasma of LRP1 knockout (hLrp1−/−) mice J.E. Wancata L. S.M. Hui D.Y. deficiency of density lipoprotein receptor related protein-1 reduces density lipoprotein and plasma levels in mice.J. Biol. Chem. 2011; 286: Full Text Full Text PDF PubMed Scopus (32) Google Scholar). The hLrp1−/− mice are also to fat and insulin resistance Y. X. Tsai S. Herz J. Low density lipoprotein receptor related protein-1 hepatic insulin resistance and hepatic 2016; Full Text Full Text PDF PubMed Scopus Google Scholar), with to steatohepatitis a fat with cholesterol S. Ding Y. X. Herz J. Hui D.Y. Low density lipoprotein receptor-related protein-1 dysfunction with cholesterol to steatohepatitis Biol. Chem. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). The mechanism the increased of hLrp1−/− mice to diet-induced and is to increased and mitochondrial permeability as a of lipid Basford J.E. A. Hui D.Y. LRP1 protein deficiency exacerbates and in Biol. Chem. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). LRP1 deficiency the functions of intracellular in the absence of lipid to be The of this study is to the of LRP1 deficiency on mitochondrial functions in hepatocytes. isolated from and hLrp1−/− mice in with glucose to the postprandial response in consumption over a showed that the basal mitochondrial lower in hLrp1−/− compared with cells and The of and the reduction in and as well as lower in with LRP1 deficiency LRP1 inactivation also to lower oxygen consumption in response to and and of the data that LRP1 deficiency reduces oxygen consumption of the acid and data to indicate that LRP1 inactivation reduces by mitochondria and in hepatocytes. analysis of from and hLrp1−/− mice with an the reduced levels of mitochondria and with LRP1 deficiency LRP1 deficiency reduces and mitochondrial isolated from hLrp1−/− mice LRP1 in and to basal oxygen consumption in the of the with on oxygen consumption in the of and in the of The data are as and by with as LRP1 deficiency reduces mitochondria and from and hLrp1−/− mice for analysis with The with and the of through through as The the expression levels of mitochondria in liver in The data are as and by for as The in mitochondrial and hLrp1−/− are to in the of as by mitochondrial in and hLrp1−/− mouse livers These that LRP1 deficiency mitochondrial functions in hepatocytes. by uptake and accumulation by mitochondria isolated from the livers of and hLrp1−/− In the isolated mitochondria in a to the of The of to mitochondria in increase in of levels in the and the of from the by mitochondria Tsai of mitochondrial in isolated mitochondria and 2018; Scholar). In increase to mitochondria isolated from hLrp1−/− mice These data the accumulation of in mitochondria isolated from hLrp1−/− mouse livers compared with that with mouse livers The increased uptake of mitochondria from hLrp1−/− mice by their lower membrane compared with mitochondria from the livers of mice complexes and are in the membrane of the and their be by of the mitochondrial membrane S.E. G. of Lipid Res. 2013; PubMed Scopus Google Scholar). of of mitochondria from and hLrp1−/− mouse livers by reduced levels of anionic including and in the mitochondria of hLrp1−/− mice compared with type in the mitochondrial membrane also mitochondria morphology S.E. G. of Lipid Res. 2013; PubMed Scopus Google Scholar), examined the livers isolated from and hLrp1−/− mice by and in mitochondrial The mitochondria in the livers of hLrp1−/− mice to be the mitochondria in mouse livers in in the of density mitochondria from and hLrp1−/− mice and These indicate that LRP1 deficiency mitochondrial morphology and of but is a of in the lower phosphatidylethanolamine and cardiolipin in the mitochondrial membrane N. S.M. and mitochondria Biol. Google Scholar, G. M. A. E. J.E. deficiency in mitochondria impairs and mitochondrial Biol. Chem. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, K. V. C. H. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, The and of is PubMed Scopus Google LRP1 deficiency mitochondria from and hLrp1−/− mice to analysis of the of the liver from and and by mitochondria from mouse and and density from the The data are as and by for from type cardiolipin and phosphatidylethanolamine to important in mitochondrial through interaction with the membrane protein Role of mitochondrial in fission and PubMed Scopus Google Scholar). also examined the levels of mitochondrial and fission in the livers of and hLrp1−/− reduction in the levels of the mitochondrial and in the livers of hLrp1−/− mice In levels of the protein-1 that is for mitochondrial fission to be significantly in hLrp1−/− livers These that the mitochondrial in hLrp1−/− be to increased mitochondrial and the in mitochondrial fusion. Additional to the mechanism by which LRP1 deficiency mitochondrial lipid and promotes mitochondrial the of (PI(4,5)P2) increase mitochondrial E. R. of from the mitochondrial membrane mitochondrial 2011; PubMed Scopus Google Scholar, X. N. S. Anderson of the plasma PubMed Scopus Google Scholar), the that LRP1 inactivation to PI(4,5)P2 in hepatocytes. of PI(4,5)P2 levels in the livers of and hLrp1−/− mice lower PI(4,5)P2 levels with LRP1 deficiency Previous studies and the of LRP1 interaction with that PI(4,5)P2 to and A. G. S. M. S. LDL receptor-related protein 1 regulates the of cell signaling in the plasma membrane Res. 2010; PubMed Scopus (15) Google and phosphatidylinositol 4-phosphate and their that PI(4,5)P2 from phosphatidylinositol 4-phosphate M. M. M.F. J. W. J. Herz J. of the density lipoprotein receptor with adaptor and functions in cellular and signal Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the liver membranes from and hLrp1−/− mice levels of with levels of and significantly lower levels of and the PIP5KL1 in the hepatic membrane of hLrp1−/− mice compared with mice Additional showed that LRP1 with 1 (PIP5KL1) as from the study M. M. M.F. J. W. J. Herz J. of the density lipoprotein receptor with adaptor and functions in cellular and signal Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), but also with LRP1 and on with LRP1 Taken together, data to indicate that LRP1 binding to PIP5KL1 recruits to the plasma membrane where it PI(4,5)P2 and the absence of LRP1 reduces PI(4,5)P2 levels to mitochondria study the importance of LRP1 for mitochondria homeostasis in the liver. The absence of LRP1 mitochondrial and mitochondrial in increased mitochondrial and that for The mitochondria in the livers of hLrp1−/− mice also an abnormal morphology and contain less anionic phospholipids, that the be to by the absence of In mitochondria in the livers of hLrp1−/− mice are in phosphatidylethanolamine in with the mitochondria in mouse anionic is in mitochondrial membrane and is important for mitochondrial fusion. with phosphatidylethanolamine deficiency are in to of the mitochondrial thereby and mitochondrial fission Role of mitochondrial in fission and PubMed Scopus Google Scholar). in the livers of hLrp1−/− mice are also in the anionic that is for of the membrane via its interaction and of the T. H. T. N. and cardiolipin in mitochondrial 2018; PubMed Scopus Google Scholar). is also in the membrane of the mitochondria where it with another to mitochondria and fission N. P.J. C.A. X. R. for and its by protein 1 a for mitochondrial membrane Biol. PubMed Scopus Google Scholar). The reduced levels of and with the increased levels of in hLrp1−/− that LRP1 regulates cardiolipin and membranes of the and its deficiency reduces cardiolipin levels but also lowers its interaction with the protein its interaction with to mitochondrial and in to the regulation of mitochondria and cardiolipin also an important role in mitochondrial via its interaction and of the transport complexes in G. V. V. G. role of cardiolipin in mitochondrial PubMed Scopus Google Scholar). the lower in hLrp1−/− also be to the reduced cardiolipin levels in the mitochondrial is in the mitochondria through cardiolipin of and Van H. Van of cardiolipin in liver PubMed Scopus Google Scholar), which in are in the plasma membrane and through and The in the also be with to phosphatidylinositol by the phosphatidylinositol levels of cardiolipin and anionic in cells are by the of lipid and of cardiolipin and anionic levels in the mitochondria is the availability of including and In of the is the that activation of an that and from levels in E. S. of by induces an increase in 1 through protein kinase and 2019; Scopus Google Scholar). activation the of also leads to of synthesis to cardiolipin biosynthesis the mechanism of the of cardiolipin biosynthesis in PubMed Scopus Google Scholar). The current study significantly lower PI(4,5)P2 levels in the livers and isolated from hLrp1−/− the reduced cardiolipin levels in the mitochondria of hLrp1−/− mice be related to reduced of PI(4,5)P2 for and cardiolipin synthesis. PI(4,5)P2 is by its synthesis through the of phosphatidylinositol and the phosphatidylinositol 4-phosphate and its by C. study the interaction LRP1 and A. G. S. M. S. LDL receptor-related protein 1 regulates the of cell signaling in the plasma membrane Res. 2010; PubMed Scopus (15) Google Scholar). of interaction activation in the livers of hLrp1−/− mice basal this study the of interaction and activation with LRP1 deficiency the reduced levels of PI(4,5)P2 and cardiolipin in hLrp1−/− mice are to PI(4,5)P2 In data indicate that LRP1 complexes with PIP5K1β and PIP5KL1 in the liver and LRP1 inactivation reduces the levels of in the plasma These are with a study the interaction LRP1 and PIP5KL1 M. M. M.F. J. W. J. Herz J. of the density lipoprotein receptor with adaptor and functions in cellular and signal Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). study of LRP1 and PIP5KL1 interaction in a also the importance of this interaction in maintaining PI(4,5)P2 levels in the liver. is to that PIP5KL1 lipid kinase but with type 1 as PIP5K1β to PI(4,5)P2 in intracellular S.J. and of a kinase Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Taken together, data indicate that in LRP1 with PIP5KL1 and recruits PIP5K1β to the plasma membrane for PI(4,5)P2 biosynthesis. The lack of LRP1 in the impairment of PI(4,5)P2 thereby the availability of for cardiolipin synthesis and mitochondrial dysfunction. LRP1 participates in PI(4,5)P2 and cardiolipin biosynthesis in is shown in the plasma membrane is a lipid that regulates including and X. N. S. Anderson of the plasma PubMed Scopus Google Scholar). In this have shown that LRP1 deficiency lipid accumulation and accelerates hepatic cell These are the of but related to increased lysosome and mitochondria permeability Basford J.E. A. Hui D.Y. LRP1 protein deficiency exacerbates and in Biol. Chem. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). of the current study that the increased of to mitochondria permeability be to the mitochondrial membrane and as a of PI(4,5)P2 availability for cardiolipin synthesis. In of the importance of PI(4,5)P2 in lysosome Y. Liu M. L. W. Zhang H. Y. Z. Li Y. H. Zhang C. Li L. Chen S. J. L. and lysosome Biol. PubMed Scopus Google Scholar), lysosome accelerates membrane permeability and cell F. R. P. membrane permeability and cell 2018; PubMed Scopus Google Scholar), the dysfunction in hLrp1−/− also be to the reduced of PI(4,5)P2 in Taken together, the current study identifies another signaling mechanism by which LRP1 regulates cell via binding and recruitment of PIP5KL1 and PIP5K1β to the membrane for PI(4,5)P2 and highlights the importance of this mechanism for maintaining the integrity and functions of intracellular organelles. and including of and are in in the (hLrp1−/−) mice by mice on a with mice on as J.E. Wancata L. S.M. Hui D.Y. deficiency of density lipoprotein receptor related protein-1 reduces density lipoprotein and plasma levels in mice.J. Biol. Chem. 2011; 286: Full Text Full Text PDF PubMed Scopus (32) Google Scholar, S. Ding Y. X. Herz J. Hui D.Y. Low density lipoprotein receptor-related protein-1 dysfunction with cholesterol to steatohepatitis Biol. Chem. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, Basford J.E. A. Hui D.Y. 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