Mouse shows links between bile acids and metabolic disorders

Published September 01 2016

Pure-background knockout mice help researchers better understand bile acid composition. PHOTO COURTESY OF JOHN CHIANG

Bile acids help us absorb dietary fats and fat-soluble nutrients. The enzyme cholesterol 7α-hydroxylase, or Cyp7a1, converts cholesterol into bile acids in the first step of the classic bile acid synthesis pathway. In a recent study published in the Journal of Lipid Research, John Chiang at Northeast Ohio Medical University and colleagues describe their characterization of a new Cyp7a1 knockout mouse. Although previous research focused on a Cyp7a1 knockout mouse with a mixed genetic background, the genetically engineered mouse in this report had a pure genetic background. The researchers found that their new knockout mouse, when compared with the original knockout mouse, survived better, had higher glucose tolerance and was less likely to develop metabolic disorders.

Chiang and colleagues were interested in understanding the influence of bile acid synthesis on liver metabolism and disease. Mice from mixed genetic backgrounds are more variable, because they come from parents of different genetic strains. These mice with mixed origin cannot be used for nutritional studies, because the results could be influenced by genes or diet. This is why the researchers created a Cyp7a1 knockout mouse that had a single genetic background for dietary studies.

With their new knockout mouse, Chiang and colleagues performed metabolic and dietary studies. They studied multiple physiological characteristics, including bile acid pool and composition, glucose tolerance, and energy metabolism under a normal or Western diet, high in fat and cholesterol. All results were compared with results using wild-type mice expressing normal levels of Cyp7a1 and earlier studies using mixed-background Cyp7a1 knockout mice.

Although mixed-background knockout mice died without dietary supplementation of bile acids or vitamins, the pure-background Cyp7a1 knockout mice were smaller but appeared normal. The mice survived despite their decreased bile acid pool size, which was 40 percent less than in wild-type mice. There were more hydrophilic bile acids and less of the cholic acid in the knockout mice, indicating a shift toward alternative bile acid synthesis.

The investigators also noted that the knockout mice showed improved glucose tolerance compared with wild-type mice when fed a normal diet. Even on a Western diet, the knockout mice did better in tolerating glucose than wild-type mice. To understand whether changes were caused by altered bile acid composition, the authors fed the mice a diet supplemented with cholic acid. They found that the changes in bile acid makeup and glucose tolerance in the knockout mice mimicked the results in wild-type mice. Therefore, changes in bile acids are responsible for both pool composition and glucose sensitivity.

While an explanation for these results is unknown, the authors suspect that fecal bile acid reabsorption from the intestine helped the knockout mice accommodate the relative decline in classic bile acid synthesis. When fed a Western diet, the mice likely reasbored the bile acids and avoided metabolic disorders and diabetes. Also, specific bile acids enriched in the pure-background knockout mice may have triggered cellular signaling in the body, causing improved glucose tolerance.

This investigation reveals how bile acid pool makeup affects glucose and energy homeostasis. It also reminds researchers to consider genetic background whenever studying mouse models. In the future, this new Cyp7a1 knockout mouse could be used to examine how bile acid composition may help protect the body from metabolic disorders.

Jennifer Shing Jennifer Shing received a Ph.D. in molecular pharmacology and experimental therapeutics from the Mayo Clinic.