We report the engineering and characterization of paraoxonase-3 knockout mice (Pon3KO). The mice were generally healthy but exhibited quantitative alterations in bile acid metabolism and a 37% increased body weight compared to the wild-type mice on a high fat diet. PON3 was enriched in the mitochondria-associated membrane fraction of hepatocytes. PON3 deficiency resulted in impaired mitochondri...

Cholestasis results in intrahepatic accumulation of cytotoxic bile acids, which cause liver damage ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver injury is counteracted by a variety of adaptive hepatoprotective mechanisms including alterations in bile acid transport, synthesis and detoxification. The underlying molecular mechanisms are mediated mainly at a transcription...

Bile acid sequestrants are nonabsorbable resins designed to treat hypercholesterolemia by preventing ileal uptake of bile acids, thus increasing catabolism of cholesterol into bile acids. However, sequestrants also improve hyperglycemia and hyperinsulinemia through less characterized metabolic and molecular mechanisms. Here, we demonstrate that the bile acid sequestrant, colesevelam, significan...

Type I human hepatic 3 -hydroxysteroid dehydrogenase (AKR1C4) plays a significant role in bile acid biosynthesis, steroid hormone metabolism, and xenobiotic metabolism. Utilization of a hidden Markov model for predictive modeling of nuclear hormone receptor response elements coupled with chromatin immunoprecipitation/microarray technology revealed a putative binding site in the AKR1C4 promoter ...

Iso-bile acids, the BP-hydroxy epimers of the normally occurring bile acids, are commonly found in the feces of man and other animals but are not present in the bile. Since isochenodeoxycholic acid and isoursodeoxycholic acid were recently isolated from the feces of patients treated with chenodeoxycholic acid or ursodeoxycholic acid, the intestinal absorption and hepatic metabolism of [24-‘4C]i...

Diets enriched in retrograded amylose (RS3) have been shown to lower serum cholesterol concentrations in rats. The possibility was tested that this hypocholesterolaemic effect of RS3 is caused by an increase in excretion of neutral steroids and/or bile acids. Six groups of ten rats were fed on purified diets containing either 12 or 140 g RS3/kg solid ingredients with and without added cholester...

The peroxisome proliferator-activated receptor(PPAR ) is a ligand-activated transcription factor that regulates the expression of a number of genes critical for fatty acid -oxidation. Because a number of substrates and intermediates of this metabolic pathway serve as ligand activators of this receptor, homeostatic control of fatty acid metabolism is achieved. Evidence also exists for PPAR -depe...

Although the principal bile acid formed from cholesterol in the rat is cholic acid (2, 3), Siperstein et al. (4) reported the formation of a small amount of lithocholic acid. Bergstriim, Sjovall, and Voltz (5) reported that lithocholic acid is not converted to cholic acid, but transformed into several unidentified acids. Subsequently, we identified P-muricholic acid (3a, S/3,7/3-trihydroxy-5/3-...

We examined how total blockage of biliary excretion, the major pathway through which cholesterol and bile acids are removed from the body, affects liver function, cholesterol and bile acid metabolism and homoeostasis. After 4 weeks of bile-duct ligation, rats showed impaired liver function, as documented by elevations in serum bilirubin and alkaline phosphatase activity. Moreover, bile-duct lig...

The metabolism of cholesterol and bile acids is tightly controlled but only partially characterized. The liver is responsible for most of the clearance and catabolism of plasma cholesterol, and the hepatocyte expression of LDL receptors is central in this process. The major pathways for net excretion of cholesterol from the body are through biliary excretion as free cholesterol or after convers...