Bile acid conjugation deficiency causes hypercholanemia, hyperphagia, islet dysfunction, and gut dysbiosis in mice
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Bile acid conjugation deficiency causes hypercholanemia, hyperphagia, islet dysfunction, and gut dysbiosis in mice. / Alrehaili, Bandar D.; Lee, Mikang; Takahashi, Shogo; Novak, Robert; Rimal, Bipin; Boehme, Shannon; Trammell, Samuel A. J.; Grevengoed, Trisha J.; Kumar, Devendra; Alnouti, Yazen; Chiti, Katya; Wang, Xinwen; Patterson, Andrew D.; Chiang, John Y. L.; Gonzalez, Frank J.; Lee, Yoon-Kwang.
I: Hepatology Communications, Bind 6, Nr. 10, 2022, s. 2765-2780.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Bile acid conjugation deficiency causes hypercholanemia, hyperphagia, islet dysfunction, and gut dysbiosis in mice
AU - Alrehaili, Bandar D.
AU - Lee, Mikang
AU - Takahashi, Shogo
AU - Novak, Robert
AU - Rimal, Bipin
AU - Boehme, Shannon
AU - Trammell, Samuel A. J.
AU - Grevengoed, Trisha J.
AU - Kumar, Devendra
AU - Alnouti, Yazen
AU - Chiti, Katya
AU - Wang, Xinwen
AU - Patterson, Andrew D.
AU - Chiang, John Y. L.
AU - Gonzalez, Frank J.
AU - Lee, Yoon-Kwang
PY - 2022
Y1 - 2022
N2 - Bile acid-CoA: amino acid N-acyltransferase (BAAT) catalyzes bile acid conjugation, the last step in bile acid synthesis. BAAT gene mutation in humans results in hypercholanemia, growth retardation, and fat-soluble vitamin insufficiency. The current study investigated the physiological function of BAAT in bile acid and lipid metabolism using Baat(-/-) mice. The bile acid composition and hepatic gene expression were analyzed in 10-week-old Baat(-/-) mice. They were also challenged with a westernized diet (WD) for additional 15 weeks to assess the role of BAAT in bile acid, lipid, and glucose metabolism. Comprehensive lab animal monitoring system and cecal 16S ribosomal RNA gene sequencing were used to evaluate the energy metabolism and microbiome structure of the mice, respectively. In Baat(-/-) mice, hepatic bile acids were mostly unconjugated and their levels were significantly increased compared with wild-type mice. Bile acid polyhydroxylation was markedly up-regulated to detoxify unconjugated bile acid accumulated in Baat(-/-) mice. Although the level of serum marker of bile acid synthesis, 7 alpha-hydroxy-4-cholesten-3-one, was higher in Baat(-/-) mice, their bile acid pool size was smaller. When fed a WD, the Baat(-/-) mice showed a compromised body weight gain and impaired insulin secretion. The gut microbiome of Baat(-/-) mice showed a low level of sulfidogenic bacteria Bilophila. Conclusion: Mouse BAAT is the major taurine-conjugating enzyme. Its deletion protected the animals from diet-induced obesity, but caused glucose intolerance. The gut microbiome of the Baat(-/-) mice was altered to accommodate the unconjugated bile acid pool.
AB - Bile acid-CoA: amino acid N-acyltransferase (BAAT) catalyzes bile acid conjugation, the last step in bile acid synthesis. BAAT gene mutation in humans results in hypercholanemia, growth retardation, and fat-soluble vitamin insufficiency. The current study investigated the physiological function of BAAT in bile acid and lipid metabolism using Baat(-/-) mice. The bile acid composition and hepatic gene expression were analyzed in 10-week-old Baat(-/-) mice. They were also challenged with a westernized diet (WD) for additional 15 weeks to assess the role of BAAT in bile acid, lipid, and glucose metabolism. Comprehensive lab animal monitoring system and cecal 16S ribosomal RNA gene sequencing were used to evaluate the energy metabolism and microbiome structure of the mice, respectively. In Baat(-/-) mice, hepatic bile acids were mostly unconjugated and their levels were significantly increased compared with wild-type mice. Bile acid polyhydroxylation was markedly up-regulated to detoxify unconjugated bile acid accumulated in Baat(-/-) mice. Although the level of serum marker of bile acid synthesis, 7 alpha-hydroxy-4-cholesten-3-one, was higher in Baat(-/-) mice, their bile acid pool size was smaller. When fed a WD, the Baat(-/-) mice showed a compromised body weight gain and impaired insulin secretion. The gut microbiome of Baat(-/-) mice showed a low level of sulfidogenic bacteria Bilophila. Conclusion: Mouse BAAT is the major taurine-conjugating enzyme. Its deletion protected the animals from diet-induced obesity, but caused glucose intolerance. The gut microbiome of the Baat(-/-) mice was altered to accommodate the unconjugated bile acid pool.
KW - N-ACYL TAURINES
KW - METABOLISM
KW - FAT
KW - DETOXIFICATION
KW - ELIMINATION
KW - RECEPTORS
KW - SECRETION
KW - PATHWAYS
KW - PLASMA
KW - SISTER
U2 - 10.1002/hep4.2041
DO - 10.1002/hep4.2041
M3 - Journal article
C2 - 35866568
VL - 6
SP - 2765
EP - 2780
JO - Hepatology Communications
JF - Hepatology Communications
SN - 2471-254X
IS - 10
ER -
ID: 316691740