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bioRxiv · 10.1101/2024.10.17.618895

Ketogenesis protects against MASLD-MASH progression through fat oxidation-independent mechanisms

Queathem, E. D.·Stagg, D.·Nelson, A.·Chaves, A. B.·Crown, S. B.·Fulghum, K.·d`Avignon, D. A.·Ryder, J. R.·Bolan, P. J.·Hayir, A.·Gillingham, J. R.·Jannatpour, S.·Rome, F. I.·Williams, A. S.·Muoio, D. M.·Ikramuddin, S.·Hughey, C. C.·Puchalska, P.·Crawford, P. A.
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Abstract

AbstractThe progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) to metabolic-dysfunction-associated steatohepatitis (MASH) involves complex alterations in both liver-autonomous and systemic metabolism that influence the livers balance of fat accretion and disposal. Here, we quantify the relative contribution of hepatic oxidative pathways to liver injury in MASLD-MASH. Using NMR spectroscopy, UHPLC-MS, and GC-MS, we performed stable-isotope tracing and formal flux modeling to quantify hepatic oxidative fluxes in humans across the spectrum of MASLD-MASH, and in mouse models of impaired ketogenesis. We found in humans with MASH, that liver injury correlated positively with ketogenesis and total fat oxidation, but not with turnover of the tricarboxylic acid cycle. The use of loss-of-function mouse models demonstrated that disruption of mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting step of ketogenesis, impairs overall hepatic fat oxidation and induces a MASLD-MASH-like phenotype. Disruption of mitochondrial {beta}-hydroxybutyrate dehydrogenase (BDH1), the terminal step of ketogenesis, also impaired fat oxidation, but surprisingly did not exacerbate steatotic liver injury. Taken together, these findings suggest that quantifiable variations in overall hepatic fat oxidation may not be a primary determinant of MASLD-to-MASH progression, but rather, that maintenance of hepatic ketogenesis could serve a protective role through additional mechanisms that extend beyond quantified overall rates of fat oxidation.

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Queathem, E. D., Stagg, D., Nelson, A., Chaves, A. B., Crown, S. B., Fulghum, K., d`Avignon, D. A., Ryder, J. R., Bolan, P. J., Hayir, A., Gillingham, J. R., Jannatpour, S., Rome, F. I., Williams, A. S., Muoio, D. M., Ikramuddin, S., Hughey, C. C., Puchalska, P., Crawford, P. A.. 2024-10-17. Ketogenesis protects against MASLD-MASH progression through fat oxidation-independent mechanisms. https://doi.org/10.1101/2024.10.17.618895

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