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

d-3-Hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded byBDH1, 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 generatedBdh1-deficient mice (Bdh1KO mice). Under normal housing conditions, with unrestricted access to food,Bdh1KO mice showed normal growth, appearance, behavior, and fertility. In contrast, fasting produced marked differences from controls. AlthoughBdh1KO mice survive fasting for at least 48 hours, blood 3HB levels remained very low inBdh1KO mice, and despite AcAc levels moderately higher than in controls, total ketone body levels inBdh1KO 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 inBdh1KO 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.