Dietary cholesterol reduces plasma triacylglycerol in apolipoprotein E-null mice: Suppression of lipin-1 and -2 in the glycerol-3-phosphate pathway

Background: Cholesterol metabolism is tightly regulated by both cholesterol and its metabolites in the mammalian liver, but the regulatory mechanism of triacylglycerol (TG) synthesis remains to be elucidated. Lipin, which catalyzes the conversion of phosphatidate to diacylglycerol, is a key enzyme involved in de novo TG synthesis in the liver via the glycerol-3-phosphate (G3P) pathway. However, the regulatory mechanisms for the expression of lipin in the liver are not well understood. Methodology/Principal Findings: Apolipoprotein E-knock out (apoE-KO) mice were fed a chow supplemented with 1.25% cholesterol (high-Chol diet). Cholesterol and bile acids were highly increased in the liver within a week. However, the amount of TG in very low-density lipoprotein (VLDL), but not in the liver, was reduced by 78%. The epididymal adipose tissue was almost eradicated in the long term. DNA microarray and real-time RT-PCR analyses revealed that the mRNA expression of all the genes in the G3P pathway in the liver was suppressed in the high-Chol diet apoE-KO mice. In particular, the mRNA and protein expression of lipin-1 and lipin-2 was markedly decreased, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which up-regulates the transcription of lipin-1, was also suppressed. In vitro analysis using HepG2 cells revealed that the protein expression of lipin-2 was suppressed by treatment with taurocholic acid. Conclusions/Significance: These data using apoE-KO mice indicate that cholesterol and its metabolites are involved in regulating TG metabolism through a suppression of lipin-1 and lipin-2 in the liver. This research provides evidence for the mechanism of lipin expression in the liver.