Apolipoproteins A-IV and A-V are acute-phase proteins in mouse HDL
Introduction
Infection and inflammation are associated with atherosclerosis. Epidemiologic studies have demonstrated that patients with Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, dental infections, chronic bronchitis, rheumatoid arthritis, systemic lupus erythematosus, and psoriasis have increased risk of atherosclerosis [1]. In addition, low-grade inflammation, as documented by increased plasma levels of C-reactive protein, has been shown to predict future risk of coronary events [2]. Histopathological data in humans and several mouse models of atherosclerosis also support a role of inflammatory process in atherogenesis. Furthermore, animals receiving repeated injections of endotoxin develop accelerated atherosclerosis [3], [4].
During infection and inflammation, a cascade of reactions occurs in the host collectively known as the acute-phase response (APR) [5]. Besides changes in acute-phase plasma proteins, the APR is also associated with systemic alterations in lipids and lipoproteins [6]. Serum triglyceride levels increase during infection and inflammation. Consequently, there is an appearance of small dense LDL [7], a particle believed to be particularly proatherogenic. Early after the onset of infection, the levels of HDL cholesterol also decrease. These changes are notably similar to those proposed to promote atherosclerosis.
During infection and inflammation, there is a reduction in levels of several plasma proteins involved in HDL-mediated reverse cholesterol transport and antioxidation, such as lecithin:cholesterol acyltransferase (LCAT), cholesterol ester transfer protein, phospholipid transfer protein, hepatic lipase, and paraoxonasel [6]. Moreover, the composition of circulating HDL, also known as acute-phase HDL, is altered. The lipid composition shows that acute-phase HDL is depleted in cholesterol ester but enriched in free cholesterol, triglyceride, and free fatty acids [8], [9]. Phospholipid content of acute-phase HDL was increased in some studies [9], [10] but decreased in others [11]. The levels of apolipoprotein J (apo J or clusterin), apo serum amyloid A (SAA), and secretory phospholipase A2 increase several fold in acute-phase HDL, whereas apo A-I, LCAT, and paraoxonasel levels decrease [6]. Acute-phase HDL is larger than normal HDL3 with its radius extending into the HDL2 range, but has a density comparable to HDL3 [12]. Because of the marked changes in HDL during the APR, acute-phase HDL behaves differently than normal HDL in terms of its protective effects against atherosclerosis [6], [13]. Our laboratory and others have shown that acute-phase HDL was less effective in removing cholesterol from macrophages, a defect that might be due to decreased LCAT levels [14], [15]. Delivery of cholesterol ester to hepatocytes is also decreased during infection due to changes in HDL composition and a reduction in hepatic scavenger receptor class B type I [16], [17]. Furthermore, reduced levels of paraoxonasel in acute-phase HDL resulted in its inability to protect LDL from oxidation [13]. These studies provide evidence that changes in the levels of proteins associated with HDL have a major impact on the various biological functions of HDL.
Identification of other HDL-associated proteins that are increased or decreased in acute-phase HDL could provide new insights into the alterations of lipoprotein metabolism and/or function during the APR. The purpose of this study was to determine if there were other changes in the protein composition of HDL during infection/inflammation using a proteomics approach. With recent improvements in isoelectric focusing and mass spectrometers, as well as the availability of genome and protein databases, a combined approach of two-dimensional gel electrophoresis and mass spectrometry has become a powerful tool to assess a global picture of proteins in samples with high sensivitity, accuracy, and reproducibility. In this study, we demonstrate increased levels of apo A-IV and apo A-V in acute-phase HDL in mice, suggesting that these two proteins are novel positive acute-phase proteins in the circulation.
Section snippets
Materials
Endotoxin (lipopolysaccharide or LPS) from Escherichia coli serotype 055:B5 was purchased from Difco Laboratories (Detroit, MI). Centricon centrifugal devices (molecular weight cutoff 10,000 Da) and C18 ZipTip were obtained from Millipore (Bedford, MA). Immobiline DryStrip, pH 3–10 NL (non-linear) and immobilized pH gradient buffer were purchased from Amersham Biosciences (Piscataway, NJ). Sequencing-grade modified trypsin was purchased from Promega (Madison, WI). Chemical supplies were
Apo A-IV and apo A-V are positive acute-phase proteins in mouse HDL
Control and acute-phase HDL were isolated from pooled mouse sera 16 h after injection of normal saline and endotoxin, respectively. The two-dimensional gel electrophoresis patterns of proteins associated with control and acute-phase HDL were visualized and compared using silver staining. A representative set is shown in Fig. 1. Certain protein spots that were consistently and unequivocally increased in acute-phase HDL compared to those in control HDL (labeled no. 1–5 in Fig. 1) were chosen
Discussion
Recent advances in isoelectric focusing and mass spectrometry, as well as the availability of databases are new tools in proteomics, which allow for the comprehensive assessment of proteins in a sample. In this study, we used such an approach to define changes in HDL-associated proteins in acute-phase HDL. Our results confirmed previous reports of increased levels of apo SAA and apo E and decreases in apo A-I and apo A-II in acute-phase HDL [11], [20], [21], [22]. A decrease in hepatic
Acknowledgements
This work was done during the tenure of a fellowship from the American Heart Association, Western States Affiliate (W.K.), and was supported by grants from the Research Service of the Department of Veterans Affairs (C.G., K.R.F.), National Institutes of Health Grants HL 31210 (J.P.K.), NCRR 01614 (K.F.M.) and RR 12961 (UCSF Mass Spectrometry Facility director: A.L. Burlingame). W.K was a recipient of the Anandamahidol Foundation Scholarship under the Royal Patronage of His Majesty the King of
References (43)
- et al.
Implication of natural killer T cells in atherosclerosis development during a LPS-induced chronic inflammation
FEBS Lett.
(2002) - et al.
HDL content and composition in acute phase response in three species: triglyceride enrichment of HDL a factor in its decrease
J. Lipid. Res.
(1996) - et al.
Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters
J. Lipid. Res.
(1993) - et al.
Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin: cholesterol acyltransferase and lipase deficiency
J. Biol. Chem.
(1989) - et al.
Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins
J. Lipid. Res.
(1989) - et al.
Effects of serum amyloid A protein (SAA) on composition, size, and density of high density lipoproteins in subjects with myocardial infarction
J. Lipid. Res.
(1985) - et al.
Cholesterol efflux by acute-phase high density lipoprotein. Role of lecithin:cholesterol acyltransferase
J. Lipid. Res.
(2001) - et al.
Regulation of scavenger receptor class B type I in hamster liver and Hep3B cells by endotoxin and cytokines
J. Lipid. Res.
(2001) - et al.
Impaired capacity of acute-phase high density lipoprotein particles to deliver cholesteryl ester to the human HUH-7 hepatoma cell line
Int. J. Biochem. Cell Biol.
(2002) - et al.
Changes in high density lipoprotein content following endotoxin administration in the mouse. Formation of serum amyloid protein-rich subtractions
J. Biol. Chem.
(1982)
Serum amyloid A-containing human high density lipoprotein 3. Density, size, and apolipoprotein composition
J. Biol. Chem.
ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response
J. Lipid. Res.
Familial apolipoprotein A-I, C-III, and A-IV deficiency and premature atherosclerosis due to deletion of a gene complex on chromosome 11
J. Biol. Chem.
Decreased HDL cholesterol levels but normal lipid absorption, growth, and feeding behavior in apolipoprotein A-IV knockout mice
J. Lipid. Res.
Identification of specific amphipathic alpha-helical sequence of human apolipoprotein A-IV involved in lecithin: cholesterol acyltransferase activation
J. Biol. Chem.
Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration
J. Biol. Chem.
Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice
Biochem. Biophys. Res. Commun.
The metabolism of liver and plasma lipids after partial hepatectomy in the rat
Biochim. Biophys. Acta
Lipoprotein synthesis and fatty acid mobilization in rats after partial hepatectomy
Biochim. Biophys. Acta
Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators
J. Biol. Chem.
The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element
J. Biol. Chem.
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Endocrinology and Metabolism Unit, Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.