Raymond F. Kauffman

Phospholipid Transfer Protein Is Regulated by Liver X Receptors in Vivo

Liver X receptors (LXR) belong to the nuclear receptor superfamily that can regulate important lipid metabolic pathways. The plasma phospholipid transfer protein (PLTP) is known to mediate transfer of phospholipids from triglyceride-rich lipoproteins to high density lipoprotein (HDL) and plays a critical role in HDL metabolism. We report here that a specific LXR agonist, T0901317, elevated HDL cholesterol and phospholipid in C57/BL6 mice and generated enlarged HDL particles that were enriched in cholesterol, ApoAI, ApoE, and phospholipid. The appearance of these HDL particles upon oral dosing of T0901317 in C57/BL6 mice was closely correlated with the increased plasma PLTP activity and liver PLTP mRNA levels. Nuclear run-on assay indicated that the effect of LXR agonist on PLTP expression was at the transcriptional level. In mouse peritoneal macrophage cells, PLTP expression was also up-regulated by the LXR/RXR (retinoid X receptor) heterodimer. However, cholesterol efflux in mouse peritoneal macrophage cells from PLTP-deficient mice (PLTP0) was not significantly different from wild type animals. Although in PLTP-deficient mice, the induction of HDL cholesterol as well as HDL particle size increase persisted, the extent of the induction was greatly attenuated. We conclude that PLTP is a direct target gene of LXRs in vivo and plays an important role in LXR agonist-mediated HDL cholesterol and size increase in mice.

Raloxifene and estrogen inhibit neointimal thickening after balloon injury in the carotid artery of male and ovariectomized female rats.

The effects of raloxifene and 17alpha-ethinyl estradiol (EE2) on intimal thickening in response to balloon injury were tested in male and ovariectomized female rats. In male rats, oral raloxifene and EE2, administered either by gavage or in the diet, inhibited arterial intimal thickening in response to balloon injury to a maximum of approximately 60 and 50%, respectively. The effect of oral raloxifene to decrease cholesterol was observed at doses (> or = 3 mg/kg/day) higher than those required to inhibit intimal thickening (> or = 0.03 mg/kg/day). Coadministration of the estrogen receptor antagonist, ICI 182,780 (5 mg/kg/day, s.c.), blocked the inhibition of balloon injury by raloxifene and EE2. Direct adventitial delivery of raloxifene (0.03 mg/kg/day) and EE2 (0.001 mg/kg/day) to the vascular wall inhibited intimal thickening by 63 and 53%, respectively. In ovariectomized female rats, oral raloxifene (0.01-3.0 mg/kg/day) and EE2 (0.08 mg/kg/day) inhibited intimal thickening to a maximum of 32 and 60%, respectively. Together, these data suggest that raloxifene and EE2, inhibit balloon arterial injury in the rat through direct effects on the vascular wall that involve the estrogen receptor and are at least partially independent of serum cholesterol.

Identification and characterization of hamster stearoyl-CoA desaturase isoforms.

Stearoyl-CoA desaturase (SCD) catalyzes the formation of monounsaturated fatty acids from saturated fatty acids. It plays a key role in lipid metabolism and energy expenditure in mammals. In mice, four SCD isoforms (SCD1–4) have been identified. Here we report the identification of cDNA sequences corresponding to SCD1, SCD2 and SCD3 of golden hamster. The deduced amino acid sequences of these hamster SCD (hmSCD) isoforms display a high degree of homologies to their mouse counterparts (mouse SCD). Polyclonal antibodies specific to rodent SCDs detected proteins of predicted size in the human embryonic kidney 293 cells transfected with hmSCD cDNAs. Microsome fractions prepared from these cells also displayed increased SCD activity versus cells transfected with vector alone. Real-time reverse transcription-polymerase chain reaction analysis revealed the highest expression of hmSCD1 in liver and adipose tissue, while the highest hmSCD2 expression was detected in the brain. Very low levels of hmSCD3 mRNA can be detected in the tissues tested. This report is the first description of three SCD isoforms in the hamster and will provide useful tools in the further study of fatty acids metabolism in this species.