Tier 3 — preclinical

α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-PGC-1α/Nrf2 pathway

Cheng D, Zhang M, Zheng Y, Wang M, Gao Y, Wang X, Liu X, Lv W, Zeng X, Belosludtsev KN, Su J, Zhao L, Liu J
Redox Biology 2024 74:103230

Bibliography

PubMed
PMID 38875959
PubMed Central
PMC11226981
DOI
10.1016/j.redox.2024.103230
Funding
Funded by the National Natural Science Foundation of China Integrated Project of Major Research Plan (No. 92249303 to Jiankang Liu and Jiacan Su) and General Projects (Nos. 32171102 and 31770917 to Jiankang Liu).
Competing interests
The authors declared no known competing financial interests or personal relationships that could have appeared to influence the work.

Study snapshot

DesignPreclinical hyperlipidemia-mouse study with hepatocyte and HepG2 mechanistic experiments.
ModelP407-induced hyperlipidemic C57BL/6J mice, primary hepatocytes and HepG2 cells.
SampleMouse intervention n=6 per reported group in the primary in-vivo experiment; additional cell experiments.
InterventionAKG 50 mg/kg/day in mice for 9 days before acute P407-induced hyperlipidemia; cell-based AKG experiments.
Duration9-day mouse pretreatment plus acute hyperlipidemia challenge.
EndpointsHepatic lipid accumulation; Mitochondrial function; Oxidative stress; AMPK-PGC-1α signaling; Nrf2 signaling; Liver injury markers

What the study showed, in plain terms

This 2024 study tested AKG in a mouse model of acute hyperlipidemia-induced fatty liver and in lipid-stressed liver cells.

AKG reduced hepatic lipid accumulation, improved mitochondrial function and redox balance, and activated AMPK-PGC-1α/Nrf2 signaling under the experimental conditions.

It is useful for mechanistic fatty-liver coverage but does not show that Ca-AKG causes weight loss or treats metabolic liver disease in humans.

Key findings

  • AKG reduced lipid accumulation in the hyperlipidemic mouse liver.
  • Mitochondrial dysfunction and oxidative stress were attenuated.
  • AMPK-PGC-1α and Nrf2 signaling contributed to the observed effects.

What this study can and cannot tell us

  • Acute preclinical model rather than chronic human metabolic disease.
  • The mouse dose and route cannot define a commercial Ca-AKG supplement dose.
  • No human oral-supplementation outcomes were measured.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology