In:
Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
Abstract:
The pathogenesis of human T2D is linked to the progression of nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). In the normal fed state, impairments of hepatocyte ketogenesis and Kupffer cell mitochondrial metabolism of ketone bodies conspire to drive hepatic injury, and lobular fibrosis - key features increasing insulin resistance and T2D. Preliminary data suggest that a local circuit of intrahepatic ketone metabolism may protect the liver from lobular injury, which involves distribution of ketone body carbon into numerous metabolic pathways. Nonetheless, the metabolic products of local hepatic ketone body metabolism that confer protection to the liver, and which are therefore linked to insulin resistance and T2D, remain unknown. Here, we use stable isotope tracing untargeted metabolomics (ITUM) to reveal the chemical space penetrated in vivo by D-[13C]β-hydroxybutyrate (D-βOHB) and its oxidized redox partner [13C] acetoacetate (AcAc). A kinetic study revealed rapid clearance (∼30 min) of both ketones from the bloodstream when introduced as intraperitoneal boluses into wild type mice. Many 13C-labeled metabolites were tissue-specific, particularly distinctly acetylated amino acids. Labeling of TCA cycle intermediates by 13C-labeled ketone bodies also varied by tissue, and by the specific labeled ketone body delivered. Finally, recurrent administration of unlabeled AcAc protected mice from high fat, fibrogenic diet-induced hepatic injury and fibrosis, while unlabeled D-βOHB exacerbated injury and fibrosis. In conclusion, the two ketone bodies AcAc and D-βOHB, strikingly exhibit distinct metabolic and phenotypic effects in the context of NAFLD/NASH, and insulin resistance. Disclosure P. Puchalska: None. J.E. Lengfeld: None. D.B. Stagg: None. P.A. Crawford: Consultant; Spouse/Partner; Medtronic.
Type of Medium:
Online Resource
ISSN:
0012-1797
,
1939-327X
Language:
English
Publisher:
American Diabetes Association
Publication Date:
2019
detail.hit.zdb_id:
1501252-9
