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  3. Deficiency of 3-hydroxybutyrate dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting

Deficiency of 3-hydroxybutyrate dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting

  • J Inherit Metab Dis. 2020 Sep;43(5):960-968. doi: 10.1002/jimd.12243.
Hiroki Otsuka 1 2,  Takeshi Kimura 1,  Yasuhiko Ago 1,  Mina Nakama 3,  Yuka Aoyama 1 4,  Elsayed Abdelkreem 1 5,  Hideki Matsumoto 1,  Hidenori Ohnishi 1,  Hideo Sasai 1 3,  Masatake Osawa 6 7,  Seiji Yamaguchi 8,  Grant A Mitchell 9,  Toshiyuki Fukao 1 3
Affiliations

Affiliations

  • 1 Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu City, Japan.
  • 2 Department of Neonatology, Gifu Prefectural General Medical Center, Gifu City, Japan.
  • 3 Clinical Genetics Center, Gifu University Hospital, Gifu City, Japan.
  • 4 Department of Biomedical Sciences, College of Life and Health Sciences, Education and Training Center of Medical Technology, Chubu University, Kasugai City, Japan.
  • 5 Department of Pediatrics, Faculty of Medicine, Sohag University, Nasser City, Egypt.
  • 6 Department of Regenerative Medicine and Applied Medical Sciences, Graduate School of Medicine, Gifu University, Gifu City, Japan.
  • 7 Gifu Center for Highly Advanced Integration of Nanosciences and Life Sciences (G-CHAIN), Gifu University, Gifu City, Japan.
  • 8 Department of Pediatrics, Graduate School of Medicine, Shimane University, Izumo City, Japan.
  • 9 Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montréal, Quebec, Canada.
PMID: 32279332 DOI: 10.1002/jimd.12243
Abstract

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.

Keywords

3-hydroxybutyrate dehydrogenase; CRISPR; fatty liver; ketone body; knockout mouse.

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