Project Details
Description
Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH) is the most common
cause of liver disease in Western countries. The severity of NAFLD in humans correlates with systemic insulin
resistance; risk of type 2 diabetes; and drives downstream complications, including cardiovascular disease,
cirrhosis, need for liver transplantation, and liver cancer. As NAFLD progresses, mitochondrial oxidative
dysfunction becomes a prominent feature, and human NAFLD exhibits progressive ketogenic deficits.
Hepatocyte ketogenesis produces the ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (D-βOHB),
which are products of incomplete fat oxidation. Measurements of ketogenesis are often used as a proxy for
hepatic fat oxidation, but these measures fail to fully report hepatic fat oxidation, because ketogenesis is blind to
complete fat oxidation in the tricarboxylic acid (TCA) cycle, which also varies over the course of NAFLD.
Published and unpublished observations generated during the previous funding cycle suggest that ketogenesis
provides vital feedback coordinating overall hepatocyte energy supply and demand. When mice are genetically
programmed to be devoid of all ketogenesis, the liver compensates by increasing TCA cycle flux, but is
predisposed to high fat diet-induced fibrosis, the feature most predictive of adverse outcomes in NASH.
Conversely, when mice are genetically programmed to produce only AcAc, but not D-βOHB [via knockout of
NAD+/NADH D-βOHB dehydrogenase (BDH1)], the liver compensates by decreasing TCA cycle flux, and is
protected from high fat diet-induced fibrosis. These findings reveal unexpected relationships between energy
supply and demand in liver that may have profound impact on how metabolic drug targets should be considered
in NAFLD. Moreover, recent observations indicate that hepatocyte derived AcAc protects against fibrosis through
oxidation in neighboring macrophages. Therefore, the central hypothesis of this proposal is that liver ketone
metabolism modulates hepatic fibrogenesis through (a) tuning hepatocyte energy supply/demand balance and
(b) metabolism of AcAc in the mitochondria of liver macrophages. This hypothesis will be tested through two
Specific Aims. First, to reveal the role of BDH1 in NASH-relevant liver injury, mice lacking BDH1 selectively in
hepatocytes will be interrogated using tracer-based mass spectrometry, nuclear magnetic resonance, and
mitochondrial bioenergetics studies, together supporting sophisticated quantifications of carbon, electron,
proton, and oxygen fluxes to construct relationships between mitochondrial efficiency and NAFLD-like
pathogenesis. In the Second Aim, tracer and flux-based approaches will quantify the effects of ketone body
exchange between hepatocytes and neighboring macrophages in NASH-like pathogenesis, using mice that lack
succinyl-CoA:3-oxoacid-CoA transferase (SCOT), which is required for AcAc oxidation in macrophages.
Together, the proposed experiments will define mechanisms through which ketone metabolism can be leveraged
to protect the liver from worsening NAFLD injury, a clear unmet need with escalating public health implications.
Status | Active |
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Effective start/end date | 8/5/11 → 6/30/24 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $351,000.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $384,375.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $319,030.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $185,236.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $57,000.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $330,600.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $382,595.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $251,416.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $424,125.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $380,000.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $487,500.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $529,554.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $519,723.00
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