Metabolic adaptation allows Amacr-deficient mice to remain symptom-free despite low levels of mature bile acids.

Bile acids play multiple roles in the physiology of vertebrates; they facilitate lipid absorption, serve as signaling molecules to control carbohydrate and lipid metabolism, and provide a disposal route for cholesterol. Unexpectedly, the α-methylacyl-CoA racemase (Amacr) deficient mice, which are unable to complete the peroxisomal cleavage of C27-precursors to the mature C24-bile acids, are physiologically asymptomatic when maintained on a standard laboratory diet. The aim of this study was to uncover the underlying adaptive mechanism with special reference to cholesterol and bile acid metabolism that allows these mice to have a normal life span. Intestinal cholesterol absorption in Amacr-/- mice is decreased resulting in a 2-fold increase in daily cholesterol excretion. Also fecal excretion of bile acids (mainly C27-sterols) is enhanced 3-fold. However, the body cholesterol pool remains unchanged, although Amacr-deficiency accelerates hepatic sterol synthesis 5-fold. Changes in lipoprotein profiles are mainly due to decreased phospholipid transfer protein activity. Thus Amacr-deficient mice provide a unique example of metabolic regulation, which allows them to have a normal lifespan in spite of the disruption of a major metabolic pathway. This metabolic adjustment can be mainly explained by setting cholesterol and bile acid metabolism to a new balanced level in the Amacr-deficient mouse.

The interplay between lipoprotein phenotypes, adiponectin, and alcohol consumption.

CONTEXT AND OBJECTIVE: Lipoproteins are involved in the pathophysiology of several metabolic diseases. Here we focus on the interplay between lipoprotein metabolism and adiponectin with the extension of alcohol intake. DESIGN AND SUBJECTS: Eighty-three low-to-moderate and 80 heavy alcohol drinkers were studied. Plasma adiponectin, other biochemical and extensive lipoprotein data were measured. Self-organizing maps were applied to characterize lipoprotein phenotypes and their interrelationships with biochemical measures and alcohol consumption. RESULTS: Alcohol consumption and plasma adiponectin had a strong positive association. Heavy alcohol consumption was associated with decreased low-density lipoprotein cholesterol (LDL-C). Nevertheless, two distinct lipoprotein phenotypes were identified, one with elevated high-density lipoprotein cholesterol (HDL-C) and decreased very-low-density lipoprotein triglycerides (VLDL-TG) together with low prevalence of metabolic syndrome, and the other vice versa. The HDL particles were enlarged in both phenotypes related to the heavy drinkers. The low-to-moderate alcohol drinkers were characterized with high LDL-C and C-enriched LDL particles. CONCLUSIONS: The analyses per se illustrated the multi-faceted and non-linear nature of lipoprotein metabolism. The heavy alcohol drinkers were characterized either by an anti-atherogenic lipoprotein phenotype (with also the highest adiponectin concentrations) or by a phenotype with pro-atherogenic and metabolic syndrome-like features. Clinically this underlines the need to distinguish the differing individual risk for lipid-related metabolic disturbances also in heavy alcohol drinkers.