Interest in intermittent fasting, ketogenic diets, and exogenous ketone therapies for prediabetes, diabetes, and nonalcoholic fatty liver disease (NAFLD) is increasing, with numerous studies showing connectivity between ketone body metabolism and NAFLD progression. Previous studies from our group showed that exogenously administered ketone bodies have divergent effects on liver health: acetoacetate (AcAc) ameliorated, while its reduced redox partner D-B-hydroxybutyrate (D-BOHB) exacerbated lobular fibrosis. Here, we study the role of hepatic redox dependent interconversion of AcAc and D-BOHB in the setting of obesity and insulin resistance. Mice deficient in hepatocyte D-BOHB dehydrogenase (BDH1) and their littermate controls were maintained on high fat western diet (WD) for 18 weeks. Post WD challenge, these mice showed similar body weight, glucose, insulin, and circulating lipids in comparison to littermate controls. While livers of hepatocyte-specific BDH1-deficient mice lost the ability to generate D-BOHB, these mice remained capable to interconvert ketone bodies in extrahepatic tissues, leading to substantial circulating D-BOHB. Hepatocyte-specific BDH1 deficient mice maintained on WD displayed diminished glucose production and hepatic oxidative fluxes. Surprisingly, BDH1 deficient mice maintained normal static energy charge and NAD+/NADH ratios. Although insulin signaling in the liver and muscle was comparable between genotypes, knockout mice exhibited improved insulin sensitivity after acute insulin challenge. In addition, livers of knockout mice showed diminished liver fibrosis and oxidative stress. Taken together, these data support the notion for salutary roles of local AcAc, but detrimental roles of local D-BOHB on liver health and suggest that hepatic BDH1-dependent ketone body interconversion is a significant contributor to liver physiology in the setting of obese insulin resistance.


D.B.Stagg: None. A.R.Seay: None. A.B.Nelson: None. D.A.D’avignon: None. C.C.Hughey: None. P.Puchalska: None. P.A.Crawford: Advisory Panel; Abbott Diabetes, Johnson & Johnson Global Services.


NIH DK091538, and NIH AG069781

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