A mouse model for α-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids

Abstract

alpha-Methylacyl-CoA racemase (Amacr) deficiency in humans leads to sensory motor neuronal and liver abnormalities. The disorder is recessively inherited and caused by mutations in the AMACR gene, which encodes Amacr, an enzyme presumed to be essential for bile acid synthesis and to participate in the degradation of methyl-branched fatty acids. To generate a model to study the pathophysiology in Amacr deficiency we inactivated the mouse Amacr gene. As per human Amacr deficiency, the Amacr(-/-) mice showed accumulation (44-fold) of C27 bile acid precursors and decreased (over 50%) primary (C24) bile acids in bile, serum and liver, however the Amacr(-/-) mice were clinically symptomless. Real-time quantitative PCR analysis showed that, among other responses, the level of mRNA for peroxisomal multifunctional enzyme type 1 (pMFE-1) was increased 3-fold in Amacr(-/-) mice. This enzyme can be placed, together with CYP3A11 and CYP46A1, to make an Amacr-independent pathway for the generation of C24 bile acids. Exposure of Amacr(-/-) mice to a diet supplemented with phytol, a source for branched-chain fatty acids, triggered the development of a disease state with liver manifestations, redefining the physiological significance of Amacr. Amacr is indispensable for the detoxification of dietary methyl-branched lipids and, although it contributes normally to bile acid synthesis from cholesterol, the putative pMFE-1-mediated cholesterol degradation can provide for generation of bile acids, allowing survival without Amacr. Based upon our mouse model, we propose elimination of phytol from the diet of patients suffering from Amacr deficiency.

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome‐deficient PEX2 Zellweger mice†

“…Mice deficient in enzymes of the peroxisomal bile acid synthesis pathway, including DBP 32 and ␣-methylacylCoA racemase (Amacr), 40 also accumulate C27 bile acids to a similar degree and have C27-conjugation defects, but fail to show the marked hepatic disease seen in the PEX2 Ϫ/Ϫ mice. These findings suggest that the more widespread biochemical disturbances associated with peroxisome assembly defects exacerbate the toxicity of bile acids and potentiate hepatic disease.…”

Metabolism of phytol to phytanic acid in the mouse, and the role of PPARα in its regulation

“…In mammals, free phytol is readily absorbed in the small intestine and is metabolized to phytanic acid, a fatty acid that accumulates in a number of metabolic disorders. Increased levels of phytanic acid in the body are toxic, so this fatty acid needs to be broken down (3)(4)(5)(6)(7)(8)(9). Because the methyl-group at the 3 position prevents b-oxidation, phytanic acid first has to undergo a round of a-oxidation.…”

“…Addition of phytol to the diet results in an increase of phytol metabolites in tissues and plasma (6,(11)(12)(13). This has been used as a model to study the effects of the accumulation of phytol metabolites on fatty acid metabolism, in particular via the activation of the nuclear hormone receptor peroxisome proliferator-activated receptor a (PPARa), which is an important transcription factor in the regulation of fatty acid metabolism.…”

A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPARα-dependent and -independent pathways

“…Thus, we mimicked the situation in patients suffering from a peroxisomal disorder, because this results in an increase of phytol metabolites in tissues and plasma (4,18). In several mouse models for peroxisomal ␤ -oxidation disorders in which branchedchain fatty acids are increased, an altered expression of various fatty acid-metabolizing enzymes has been reported (19)(20)(21)(22).…”