ABSTRACT
Peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the nuclear receptor superfamily that regulates multiple target genes involved in lipid metabolism. Cholesterol ester transfer protein (CETP) is a secreted glycoprotein that modifies high-density lipoprotein (HDL) particles. In humans, plasma CETP activity is inversely correlated with HDL cholesterol levels. We report here that PPARalpha agonists increase CETP mRNA, protein and accordingly its activity. In a human CETP transgenic animal model harboring the natural flanking regions (Jiang et al. in J Clin Investigat 90:1290-1295, 1992), both fenofibrate and a specific synthetic PPARalpha agonist LY970 elevated human CETP mRNA in liver, serum protein and CETP activity. In hamsters, the endogenous liver CETP mRNA level and the serum CETP activity were dose-dependently upregulated by fenofibrate. In addition Wy14643, a PPARalpha agonist, also significantly elevated CETP mRNA and activity. In a carcinoma cell line of hepatic origin, HepG2 cells, overexpression of PPARalpha resulted in increased CETP mRNA and agonist treatment further elevated CETP mRNA levels. We conclude that PPARalpha agonists upregulate CETP expression and activity and may play an important role in PPARalpha (agonist mediated HDL cholesterol homeostasis in humans.
Subject(s)
Cholesterol Ester Transfer Proteins/metabolism , PPAR alpha/agonists , PPAR alpha/metabolism , Animals , Cells, Cultured , Cholesterol Ester Transfer Proteins/drug effects , Cholesterol Ester Transfer Proteins/genetics , Cricetinae , Fenofibrate/pharmacology , Humans , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Transgenic , PPAR alpha/genetics , RNA, Messenger/biosynthesisABSTRACT
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.
