Role of AMACR (α-methylacyl-CoA racemase) and MFE-1 (peroxisomal multifunctional enzyme-1) in bile acid synthesis in mice

Abstract

Cholesterol is catabolized to bile acids by peroxisomal β-oxidation in which the side chain of C27-bile acid intermediates is shortened by three carbon atoms to form mature C24-bile acids. Knockout mouse models deficient in AMACR (α-methylacyl-CoA racemase) or MFE-2 (peroxisomal multifunctional enzyme type 2), in which this β-oxidation pathway is prevented, display a residual C24-bile acid pool which, although greatly reduced, implies the existence of alternative pathways of bile acid synthesis. One alternative pathway could involve Mfe-1 (peroxisomal multifunctional enzyme type 1) either with or without Amacr. To test this hypothesis, we generated a double knockout mouse model lacking both Amacr and Mfe-1 activities and studied the bile acid profiles in wild-type, Mfe-1 and Amacr single knockout mouse line and Mfe-1 and Amacr double knockout mouse lines. The total bile acid pool was decreased in Mfe-1-/- mice compared with wild-type and the levels of mature C24-bile acids were reduced in the double knockout mice when compared with Amacr-deficient mice. These results indicate that Mfe-1 can contribute to the synthesis of mature bile acids in both Amacr-dependent and Amacr-independent pathways.

Hepatic dysfunction in peroxisomal disorders

“…Liver weight is also increased in Amacr -/-and in double Amacr -/-/Mfp1 -/-mice [49] and, upon aging, liver tumors develop more frequently in both models. The space of Disse located between sinusoidal endothelial cells and hepatocytes was enlarged in Amacr -/-mice and disrupted in double Amacr -/-/Mfp1 -/-mice [49]. The mild pathology in Amacr -/-mice is likely due to a metabolic adaptation resulting in less intestinal cholesterol uptake and increased C27-bile acid excretion [50].…”

“…Mice lacking ABCD3 have a twofold increased liver size but neither steatosis nor other pathologies were found [35]. Liver weight is also increased in Amacr -/-and in double Amacr -/-/Mfp1 -/-mice [49] and, upon aging, liver tumors develop more frequently in both models. The space of Disse located between sinusoidal endothelial cells and hepatocytes was enlarged in Amacr -/-mice and disrupted in double Amacr -/-/Mfp1 -/-mice [49].…”

“…The mild pathology in Amacr -/-mice is likely due to a metabolic adaptation resulting in less intestinal cholesterol uptake and increased C27-bile acid excretion [50]. At closer inspection of MFP1 deficient mice, portal degeneration was seen in adult animals (3.5 month old) and increased liver enzymes in plasma point to liver damage [49].…”

Phytol is lethal for Amacr-deficient mice

“…The first Amacr deficient mouse became sick already after two weeks on the phytol diet, and within 36 weeks all of the Amacr deficient mice reached the end-point, whereas wild-type mice on the phytol diet thrived. On a standard laboratory diet that is low in α˗methyl branched fatty acids, the life span of Amacr −/− mice was comparable to wild-type controls [11]. Amacr −/− male mice seem to be more sensitive to phytol than Amacr −/− female mice based on mortality pattern ( Fig.…”

“…A difference between wild-type mouse sexes was also apparent in this study, but it seems that female Amacr−/− mice tolerated phytol better than male Amacr−/− mice. Previously it was shown that Amacr−/− mice have a normal life span on a control diet [11].…”