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Deficiency of 3‐hydroxybutyrate dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting
Author(s) -
Otsuka Hiroki,
Kimura Takeshi,
Ago Yasuhiko,
Nakama Mina,
Aoyama Yuka,
Abdelkreem Elsayed,
Matsumoto Hideki,
Ohnishi Hidenori,
Sasai Hideo,
Osawa Masatake,
Yamaguchi Seiji,
Mitchell Grant A.,
Fukao Toshiyuki
Publication year - 2020
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12243
Subject(s) - ketogenesis , medicine , endocrinology , ketone bodies , butyrate , steatosis , dehydrogenase , enzyme , chemistry , metabolism , biology , biochemistry , fermentation
d ‐3‐Hydroxy‐n‐butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1 , catalyzes the reversible reduction of acetoacetate (AcAc) to 3‐hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1 ‐deficient mice ( Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior, and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO mice survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total ketone body levels in Bdh1 KO mice were significantly lower than in wild‐type (WT) mice after 16, 24, and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of ketogenesis for lipid energy balance in the liver.