Ketohexokinase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and in vitro mechanistic study without human data
PubMed 36822479 · doi:10.1016/j.jhep.2023.02.010
What was done
Researchers investigated how dietary fructose worsens high-fat diet (HFD)-induced metabolic dysfunction using 6-week-old male C57Bl/6J mice fed normal chow or a HFD, supplemented with regular, fructose-, or glucose-sweetened water. Additional in vivo models included mice with hepatic overexpression of ketohexokinase-C (KHK-C), liver-specific carnitine palmitoyltransferase 1a (CPT1α) knockout mice, genetically obese (db/db) mice, and lipodystrophic FIRKO mice. In vitro, AML12 hepatocytes were engineered to overexpress KHK-C via lentivirus, while CRISPR-Cas9 was used to knock down CPT1α. Outcomes were evaluated using metabolomics, electron microscopy, mitochondrial substrate phenotyping, proteomics, and acetylome analysis.
What was found
The abstract reports directional findings without numerical values. Fructose supplementation in chow-fed mice and fructose or glucose supplementation in HFD-fed mice increased KHK-C. Elevated KHK-C was associated with increased lipogenic proteins (such as ACLY) without altering mRNA expression. Increased KHK-C correlated with acetylation of CPT1α at K508 and reduced CPT1α protein in vivo; this inverse correlation was also observed in db/db and FIRKO mice. In vitro, KHK-C overexpression reduced CPT1α, increased triglyceride accumulation, increased global protein acetylation, and decreased levels of the cytoplasmic deacetylase SIRT2. Knockdown of CPT1α partially replicated the KHK-C phenotype.
Why it matters
This study identifies a post-translational mechanism through which fructose-driven KHK-C increases global protein acetylation and downregulates SIRT2, suppressing CPT1α-mediated fatty acid oxidation alongside promoting lipogenesis.
Limits
No exact sample sizes, numerical values, or effect sizes are provided in the abstract. All findings are derived from rodent and cell culture models, lacking human clinical validation.
Cited by
- supports Fructose promotes liver fat accumulation while simultaneously blocking hepatic fat oxidation.