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

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.

Diminished ketone interconversion, hepatic TCA cycle flux, and glucose production in D-β-hydroxybutyrate dehydrogenase hepatocyte-deficient mice

“…Despite a modest increase in circulating AcAc, KO mice demonstrate decreases in both circulating βOHB and TKB levels in the fasting and to a lesser extent, fed states. These changes in circulating ketones are similar to those recently published in a total BDH1 knockout mouse model [ 45 ]. Although BDH1 is not the rate-limiting step in ketogenesis, our portal vein perfusion data indicate that this decrease in circulating ketones in KO mice reflects a modest decrease in overall hepatic ketogenesis.…”

The transcriptional repressor Zfp125 modifies hepatic energy metabolism in response to fasting and insulin resistance

“…This is reminiscent of the observation that mice treated with Hmgcs2 antisense oligonucleotide (Cotter et al, 2014;Geisler et al, 2019) as well as the Bdh1-deficient mice (Bdh1KO) (Otsuka et al, 2020), also exhibit impaired synthesis of BHB. When fasted, these animals exhibited increased hepatic gluconeogenesis, mild hyperglycemia, and hepatic steatosis (Otsuka et al, 2020); all these features are caused by liver-specific Zfp125 expression ( Fig. 1) (Fernandes et al, 2018b).…”

Development and genetics of red coloration in the zebrafish relative Danio albolineatus

“…The second red-deficient mutant, bdh1a , encodes 3-hydroxybutyrate dehydrogenase type 1a, a short-chain dehydrogenase/reductase. Homologues of this gene in mammals are known to interconvert hydroxyl and ketone groups, and in particular acetoacetate and 3-hydroxybutyrate, two major ketone bodies ( Green et al, 1996 ; Langston et al, 1996 ; Persson et al, 2009 ; Otsuka et al, 2020 ). Although not implicated previously in carotenoid processing or red coloration, transcripts of a homologous gene were enriched in orange skin of clownfish Amphiprion ocellaris ( Salis et al, 2019 ).…”