Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis

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The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing globally. NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). NASH is the pathological form of the disease characterized by liver steatosis, inflammation, cell injury, and fibrosis. A fundamental contributor to NASH is the imbalance between lipid accretion and disposal. The accumulation of liver lipids precipitates lipotoxicity and the inflammatory contributions to disease progression. This review defines the role of dysregulated of lipid disposal in NAFLD pathophysiology. The characteristic changes in mitochondrial oxidative metabolism pathways and the factors promoting these changes across the spectrum of NAFLD severity are detailed. This includes pathway-specific and integrative perturbations in mitochondrial β-oxidation, citric acid cycle flux, oxidative phosphorylation, and ketogenesis. Moreover, well-recognized and emerging mechanisms through which dysregulated mitochondrial oxidative metabolism mediates inflammation, fibrosis, and disease progression are highlighted.

Original languageEnglish (US)
Article number159209
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Issue number11
StatePublished - Nov 2022

Bibliographical note

Funding Information:
This work was supported by NIH grants DK091538 (PAC) and AG069781 (PAC), and an American Cancer Society Institutional Research Grant IRG-21-049-61-IRG131 (CCH). Figures were created with .

Publisher Copyright:
© 2022 Elsevier B.V.


  • Citric acid cycle
  • Inflammation
  • Ketogenesis
  • Lipid metabolism
  • Non-alcoholic steatohepatitis
  • Oxidative phosphorylation


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