2. Academic Validation
  3. Natural Linoleic Acid from Marine Fungus Eutypella sp. F0219 Blocks KEAP1/NRF2 Interaction and Ameliorates MASLD by Targeting FABP4

Natural Linoleic Acid from Marine Fungus Eutypella sp. F0219 Blocks KEAP1/NRF2 Interaction and Ameliorates MASLD by Targeting FABP4

  • Free Radic Biol Med. 2024 Sep 17:224:630-643. doi: 10.1016/j.freeradbiomed.2024.09.019.
Chen-Yan Wu 1,  Yue Chen 1,  Meng-Ting Chen 1,  Ting-Ting Fu 1,  Jin Liu 1,  Fei-Fei Liu 1,  Cong-Jun Xu 1,  Wan-Shan Li 2,  Bao-Li Li 1,  Zhong-Ping Jiang 3,  Yong Rao 4,  Ling Huang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, China.
  • 2 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education and Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, 571158, China.
  • 3 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, China. Electronic address: zpjiang@hainanu.edu.cn.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, China. Electronic address: raoyong@hainanu.edu.cn.
  • 5 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570200, China. Electronic address: Linghuang@hainanu.edu.cn.
PMID: 39299527 DOI: 10.1016/j.freeradbiomed.2024.09.019
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.

Keywords

FABP4; KEAP1; Lipotoxicity; MASLD; NRF2.

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