Mice with Bile acid-CoA: amino acid N-acyltransferase deletion are Protected from Obesity

Background Bile acid-CoA: amino acid N-acyltransferase (BAAT) is the enzyme which is responsible for bile acid (BA) conjugation with glycine and taurine in the final step of bile acid synthesis in humans. More than 98% of BA conjugation occurs in the liver. BAAT deficiency affects lipid homeostasis in the whole body. BA conjugation is essential to improve fat solubility and counteract passive diffusion in intestine by reducing their pKa values. Thus, the absence of conjugated BAs in the duodenum will affect the absorption of dietary fat and lipid soluble vitamins. Aim We aimed to investigate the physiological effects of BAAT deficiency on the mice in diet-induced obesity using BAAT knockout (BAAT KO) mice. Methods Male BAAT KO mice and their littermate WT control mice were fed a WD for 15 weeks. LC-MS were used to analyze BAs in the gallbladder. Body weight, EchoMRI analysis, CLAMS, gene expression, and plasma analysis were used to discern the severity of fat malabsorption that is associated with the deficiency of BAAT when mice were challenged with a WD. Results Total BA levels in serum, liver, and urine were induced in KO mice. Levels of unconjugated BAs were significantly higher and taurine conjugated but not glycine conjugated BAs were almost completely absent in the gallbladders of KO mice. Cyp7a1, Bsep, Abca1a, Abcc4, Papss2, and Sult2a1, genes involved in BA metabolism, were strongly upregulated in the livers of KO mice. Triglyceride levels in the liver exhibited a significant reduction while fecal total lipids levels were increased in KO mice compared with controls after WD challenge. CLAMS data displays an increased in the respiratory exchange ratio and food intake in KO mice when they were on WD. Their BW gains were also significantly impaired during gestation period. Conclusion BAAT KO mice fail to gain body weight either during gestation or when they consumed a WD due to the defect in fat absorption, which is caused by conjugated bile acid deficiency. BAATKO mice is a novel model to study bile acid and lipid metabolism. Support or Funding Information This work was supported by a bridge fund (Y.K.L) from NEOMED.