Changes in metabolism, composition, and function of high-density lipoproteins during the acute-phase response

Multiple changes in high-density lipoprotein (HDL) occur during the host response to infection and inflammation. Using in vivo models of hamsters and mice injected with endotoxin, and an in vitro model of cells treated with endotoxin and cytokines, changes in the metabolism, composition, and function of HDL during the acute-phase response (APR) were studied. Endotoxin decreased levels of two ATP-binding cassette (ABC) transporters involved in cholesterol efflux, ABCA1 and ABCG1, in J774 murine macrophages. Cholesterol flux experiments showed that acute-phase HDL, isolated from animals injected with endotoxin, was less efficient in promoting cholesterol removal from cells. The defect was due to both decreased cholesterol efflux and increased cholesterol influx, causing cholesterol accumulation in cells. Lower activity of lecithin: cholesterol acyltransferase in acute-phase HDL was likely the mechanism. In rodent liver, endotoxin downregulated levels of scavenger receptor class B type I, which resulted in a decrease in cholesterol ester uptake into hepatocytes. In addition, endotoxin decreased hepatic mRNA levels of ABCG5 and ABCG8, two transporters proposed to efflux sterols into the bile. Collectively, these data show that many steps of reverse cholesterol transport are impaired during the APR. The protein composition of acute-phase HDL was also examined using a combination of two-dimensional gel electrophoresis, mass spectrometry, and immunoblot analysis. Acute-phase HDL had increased levels of apolipoprotein (apo) A-IV and AN but decreased apo A-II. While levels of apo C-I, C-II, and C-III were decreased in acute-phase HDL, an increase was observed in acute-phase VLDL, suggesting a redistribution. Finally, hamster apo A-I immunoaffinity columns were developed to purify HDL. A protein not previously known to be associated with HDL, parotid secretory protein (PSP), was identified and the cDNA of hamster PSP was cloned. In addition to the salivary glands, PSP was expressed in the lung, skin, and gonads. PSP sequence contains a region homologous to an amino terminus of a family of lipid transfer proteins including bactericidal/permeability-increasing protein, lipopolysaccharide binding protein, cholesterol ester transfer protein, and phospholipid transfer protein. The levels of PSP were increased in hamster HDL after endotoxin injection, suggesting that PSP might be involved in the innate immune response.