A medium-chain fatty acid analogue prevents hepatosteatosis and decreases inflammatory lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis.

Autor: Cho BS; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Fligor SC; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Fell GL; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Secor JD; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Tsikis ST; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Pan A; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America., Yu LJ; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Ko VH; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Dao DT; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Anez-Bustillos L; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Hirsch TI; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Lund J; Department of Pharmacy, Section for Pharmacology and Pharmaceutical Biosciences, University of Oslo, Oslo, Norway., Rustan AC; Department of Pharmacy, Section for Pharmacology and Pharmaceutical Biosciences, University of Oslo, Oslo, Norway., Fraser DA; NorthSea Therapeutics, Amsterdam, Netherlands., Gura KM; Harvard Medical School, Boston, Massachusetts, United States of America.; Department of Pharmacy and the Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, United States of America., Puder M; Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 Dec 01; Vol. 18 (12), pp. e0295244. Date of Electronic Publication: 2023 Dec 01 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0295244
Abstrakt: Background: Parenteral (intravenous) nutrition is lifesaving for patients with intestinal failure, but long-term use of parenteral nutrition often leads to liver disease. SEFA-6179 is a synthetic medium-chain fatty acid analogue designed to target multiple fatty acid receptors regulating metabolic and inflammatory pathways. We hypothesized that SEFA-6179 would prevent hepatosteatosis and lipotoxicity in a murine model of parenteral nutrition-induced hepatosteatosis.
Methods: Two in vivo experiments were conducted. In the first experiment, six-week-old male mice were provided an ad lib fat-free high carbohydrate diet (HCD) for 19 days with orogastric gavage of either fish oil, medium-chain triglycerides, or SEFA-6179 at a low (0.3mmol/kg) or high dose (0.6mmol/kg). In the second experiment, six-week-old mice were provided an ad lib fat-free high carbohydrate diet for 19 days with every other day tail vein injection of saline, soybean oil lipid emulsion, or fish oil lipid emulsion. Mice then received every other day orogastric gavage of medium-chain triglyceride vehicle or SEFA-6179 (0.6mmol/kg). Hepatosteatosis was assessed by a blinded pathologist using an established rodent steatosis score. Hepatic lipid metabolites were assessed using ultra-high-performance liquid chromatography-mass spectrometry. Effects of SEFA-6179 on fatty acid oxidation, lipogenesis, and fatty acid uptake in human liver cells were assessed in vitro.
Results: In the first experiment, mice receiving the HCD with either saline or medium-chain triglyceride treatment developed macrovesicular steatosis, while mice receiving fish oil or SEFA-6179 retained normal liver histology. In the second experiment, mice receiving a high carbohydrate diet with intravenous saline or soybean oil lipid emulsion, along with medium chain triglyceride vehicle treatment, developed macrovescular steatosis. Treatment with SEFA-6179 prevented steatosis. In each experiment, SEFA-6179 treatment decreased arachidonic acid metabolites as well as key molecules (diacylglycerol, ceramides) involved in lipotoxicity. SEFA-6179 increased both β- and complete fatty oxidation in human liver cells, while having no impact on lipogenesis or fatty acid uptake.
Conclusions: SEFA-6179 treatment prevented hepatosteatosis and decreased toxic lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. An increase in both β- and complete hepatic fatty acid oxidation may underlie the reduction in steatosis.
Competing Interests: This study was primarily funded via a sponsored research agreement with NorthSea Therapeutics. SEFA-6179 is a drug under clinical development by NorthSea Therapeutics for intestinal failure-associated liver disease. Dr. Fraser is the Chief Scientific Officer of NorthSea Therapeutics. Drs. Puder and Gura are external consultants for Northsea Therapeutics. The study was designed in consultation with NorthSea Therapeutics, but final study design decisions were made by Dr. Puder. NorthSea Therapeutics and Dr. Fraser were not involved in the collection, analysis, or interpretation of data. These competing interests do not alter the adherence to all PLOS ONE policies on sharing data and materials.
(Copyright: © 2023 Cho et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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