The contribution of cholesterol-7alpha-hydroxylase, paraoxonase-1, and thioredoxin-interacting protein in lipid metabolism

The studies presented herein examine the role of cholesterol-7[alpha]-hydroxylase, paraoxonase-1, and thioredoxin-interacting protein in various aspects of lipid metabolism. Cholesterol-7[alpha]-hydroxylase (CYP7A1) is responsible for the conversion of cholesterol into bile acids. Hepatic over-expression of CYP7A1 maintained cholesterol homeostasis in low-density lipoprotein receptor (LDLR)-deficient mice that were fed a cholesterol-enriched diet. The presence of the CYP7A1 transgene altered the expression of many genes in the liver and the ileum. In particular, the expansion of the bile acid pool reduced ileal expression of Niemann-Pick C1 -like 1 (NPC1L1), in an farsenoid X receptor (FXR)- independent manner, which was associated with diminished cholesterol absorption. The expression of paraoxonase 1 (PON1) correlates inversely with the formation of atherosclerotic lesions. Through the activation of FXR, bile acids increase the ileal expression of fibroblast growth factor 15 (FGF15) which binds to fibroblast growth factor receptor 4 (FGFR4) leading to diminished hepatic expression of PON1 and CYP7A1. In contrast to hepatic PON1 mRNA expression, a strong correlation exists between plasma PON1 activity levels and plasma HDL cholesterol levels. Indeed, mice that have virtually undetectable levels of plasma HDL cholesterol, such as ATP Binding Cassette Protein A1 (ABCA1)-deficient mice, have only minute plasma PON1 protein levels. However, the administration of reconstituted HDL to ABCA1-deficient mice is sufficient to generate a transient increase in mature HDL particles containing PON1. Disruption of thioredoxin-interacting protein (Txnip) in mice leads to metabolic abnormalities, especially in the fasted state. Fasting Txnip knockout mice display high plasma triglyceride and ketone levels, as well as decreased plasma glucose levels. The hypertriglyceridemia observed in Txnip knockout mice is due to an impaired clearance of triglycerides, which correlated with decreased LPL mRNA expression and decreased LPL activity in the skeletal muscle and heart. Additional metabolic alterations in fasting Txnip knockout mice include impaired AMP-activated protein kinase (AMPK) activation and diminished oxidative capacity of glucose, 3-hydroxybutyrate, and fatty acid