Excessive Hepatic Mitochondrial TCA Cycle and Gluconeogenesis in Humans with Nonalcoholic Fatty Liver Disease
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Approximately one-third of the U.S. population has nonalcoholic fatty liver disease (NAFLD), a condition closely associated with insulin resistance and increased risk of liver injury. Dysregulated mitochondrial metabolism is central in these disorders, but the manner and degree of dysregulation are disputed. This study tested whether humans with NAFLD have abnormal in vivo hepatic mitochondrial metabolism. Subjects with low (3.0%) and high (17%) intrahepatic triglyceride (IHTG) were studied using (2)H and (13)C tracers to evaluate systemic lipolysis, hepatic glucose production, and mitochondrial pathways (TCA cycle, anaplerosis, and ketogenesis). Individuals with NAFLD had 50% higher rates of lipolysis and 30% higher rates of gluconeogenesis. There was a positive correlation between IHTG content and both mitochondrial oxidative and anaplerotic fluxes. These data indicate that mitochondrial oxidative metabolism is ~2-fold greater in those with NAFLD, providing a potential link between IHTG content, oxidative stress, and liver damage.
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In humans with NAFLD, a rapid rise in liver triglycerides is associated with stimulated mitochondrial oxidative function, suggesting compensatory β-oxidation.
“Interestingly, in work performed in humans with NAFLD, a rapid elevation of liver levels of triglycerides was observed and is associated with stimulation of mitochondrial oxidative function165, suggesting a compensatory stimulation of mitochondrial β-oxidation.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [165]
Potential mechanisms to explain the beneficial effects of targeting mitochondrial fatty acid oxidation could be the concomitant enhancement of hepatic ketone bodies, CO2, acid soluble products, ATP production, and endergonic processes (e.g., gluconeogenesis) seen in previous publications.
“Potential mechanisms to explain the beneficial effects of targeting mitochondrial FAO could be the concomitant enhancement of hepatic ketone bodies, CO2, acid soluble products, ATP production, and endergonic processes (*e.g.,* gluconeogenesis) seen in previous publications ([38](#B38), [130](#B130), [158](#B158)).”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [158]
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- Authors
- Sunny, N. E., Parks, E. J., Browning, J. D., & Burgess, S. C.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Browning, Jeffrey D.
- Burgess, Shawn C.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 14
- Issue
- 6
- Pages
- 804-810
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3658280
- OpenAlex
- W1985236262
- Cited by
- 672
- References
- 47
- Citations by year
- 2026: 41 · 2025: 60 · 2024: 43 · 2023: 58 · 2022: 55 · 2021: 62 · 2020: 52 · 2019: 54 · 2018: 43 · 2017: 33 · 2016: 50 · 2015: 43 · 2014: 29 · 2013: 28 · 2012: 20
- FWCI
- 18.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Texas Southwestern Medical Center
- Georgia Clinical and Translational Science Alliance (UL1RR024982)
- National Institutes of Health (1tl1dk081181-01, UL1TR000451)
- National Institute of Diabetes and Digestive and Kidney Diseases (TL1-DK081181, P01DK058398, PL1DK081182, PL1DK081183, RL1DK081187, K23DK074396, R01DK087977, RL9DK081180, R01DK078184)
- National Institute of Dental and Craniofacial Research (UL1DE019584)
- National Center for Research Resources (UL1RR024982, UL1RR024923, P20RR020691)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- non-alcoholic fatty liver disease, TCA cycle, gluconeogenesis, anaplerosis, ketogenesis, intrahepatic triglyceride, lipolysis, hepatic glucose production, insulin resistance, oxidative stress, liver injury
- MeSH terms
- Adult, Black or African American, Carbon Isotopes, Citric Acid Cycle, Deuterium, Fatty Liver, Female, Gluconeogenesis, Glucose, Hispanic or Latino, Humans, Lipolysis, Liver, Male, Middle Aged, Mitochondria, Non-alcoholic Fatty Liver Disease
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