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Updated: Jun 12, 2025
Lipid Supplementation for Longevity and Gene Transcriptional Analysis in Caenorhabditis elegans
Published on: December 9, 2022
Natural linoleic acid from marine fungus Eutypella sp. F0219 blocks KEAP1/NRF2 interaction and ameliorates MASLD by
Chen-Yan Wu1, Yue Chen1, Meng-Ting Chen1
1Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570200, China.
Abstract:
Ectopic lipid accumulation induced lipotoxicity plays a crucial role in exacerbating the development of metabolic dysfunction-associated steatotic liver disease (MASLD), which affects over 30 % of the worldwide population and 85 % of the obese population. The growing demand for effective therapeutic agents highlights the need for high-efficacy lipotoxicity ameliorators and relevant therapeutic targets in the fight against MASLD. This study aimed to discover natural anti-lipotoxic and anti-MASLD candidates and elucidate the underlying mechanism and therapeutic targets. Utilizing palmitic acid (PA)-induced HepG-2 and primary mouse hepatocyte models, we identified linoleic acid (HN-002), a ligand of fatty acid binding protein 4 (FABP4), from the marine fungus Eutypella sp. F0219. HN-002 dose-dependently prevented lipid overload-induced hepatocyte damage and lipid accumulation, inhibited fatty acid esterification, and ameliorated oxidative stress. These beneficial effects were associated with improvements in mitochondrial adaptive oxidation. HN-002 treatment enhanced lipid transport into mitochondria and oxidation, inhibited mitochondrial depolarization, and reduced mitochondrial ROS (mtROS) level in PA-treated hepatocytes. Mechanistically, HN-002 treatment disrupted the interaction between KEAP1 and NRF2, leading to NRF2 deubiquitylation and nuclear translocation, which activated beneficial metabolic regulation. In vivo, HN-002 treatment (20 mg/kg/per 2 days, i. p.) for 25 days effectively reversed hepatic steatosis and liver injury in the fast/refeeding plus high-fat/high-cholesterol diet induced MASLD mice. These therapeutic effects were associated with enhanced mitochondrial adaptive oxidation and activation of NRF2 signaling in the liver. These data suggest that HN-002 would be an interesting candidate for MASLD by improving mitochondrial oxidation via the FABP4/KEAP1/NRF2 axis. The discovery offers new insights into developing novel anti- MASLD agents derived from marine sources.
Insights
A marine fungus compound, linoleic acid (HN-002), combats metabolic dysfunction-associated steatotic liver disease (MASLD) by enhancing mitochondrial oxidation and activating NRF2 signaling. This natural agent shows promise for treating liver steatosis and injury.
Area of Science:
- Marine biotechnology
- Hepatology
- Molecular biology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) affects a significant global population, driven by ectopic lipid accumulation and lipotoxicity.
- Current therapeutic strategies for MASLD are limited, necessitating the discovery of novel agents and targets to combat liver steatosis and injury.
Purpose of the Study:
- To identify natural compounds with anti-lipotoxic and anti-MASLD properties from marine sources.
- To elucidate the underlying molecular mechanisms and therapeutic targets of identified candidates.
Main Methods:
- Utilized palmitic acid (PA)-induced HepG-2 and primary mouse hepatocyte models to screen for anti-lipotoxic agents.
- Investigated the effects of linoleic acid (HN-002) on lipid metabolism, oxidative stress, and mitochondrial function.
- Examined the impact of HN-002 on the KEAP1/NRF2 signaling pathway.
- Evaluated the therapeutic efficacy of HN-002 in a mouse model of MASLD.
Main Results:
- Identified linoleic acid (HN-002) from the marine fungus Eutypella sp. F0219 as a potent anti-lipotoxic agent.
- HN-002 dose-dependently protected hepatocytes from PA-induced damage, reduced lipid accumulation, inhibited fatty acid esterification, and ameliorated oxidative stress.
- HN-002 enhanced mitochondrial adaptive oxidation, improved mitochondrial function, and reduced mitochondrial reactive oxygen species (mtROS).
- Mechanistically, HN-002 activated the NRF2 pathway by disrupting the KEAP1-NRF2 interaction.
- In vivo studies demonstrated that HN-002 reversed hepatic steatosis and liver injury in MASLD mice, associated with enhanced mitochondrial oxidation and NRF2 activation.
Conclusions:
- Linoleic acid (HN-002) derived from marine fungus Eutypella sp. F0219 is a promising therapeutic candidate for MASLD.
- HN-002 exerts its beneficial effects by improving mitochondrial oxidation and activating the NRF2 signaling pathway via the FABP4/KEAP1/NRF2 axis.
- This discovery provides novel insights into marine-derived agents for MASLD treatment.
