Journal Article

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

Ko, Victoria H., Rustan, Arild C., Cho, Bennet S., Gura, Kathleen M., Yu, Lumeng J., Lund, Jenny, Tsikis, Savas T., Anez-Bustillos, Lorenzo, Fraser, David A., Puder, Mark, Fell, Gillian L., Dao, Duy T., Hirsch, Thomas I., Secor, Jordan D., Pan, Amy, Fligor, Scott C.

2023

Overview

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. 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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Advertising executives / Amino acids / Animal experimentation / Animal models / Animals / Arachidonic acid / Biocompatibility / Carbohydrates / Care and treatment / Ceramides / Chromatography / Chronic illnesses / Complications and side effects / Diet / Diglycerides / Disease Models, Animal / Emulsions / Experiments / Fat Emulsions, Intravenous / Fatty acids / Fatty Acids - metabolism / Fatty liver / Fatty Liver - pathology / Fish / Fish Oils / Gallbladder diseases / Health aspects / Hepatocytes / High carbohydrate diet / High fat diet / High performance liquid chromatography / Histology / Hospitals / Humans / In vivo methods and tests / Inflammation / Intravenous administration / Lipids / Lipogenesis / Liquid chromatography / Liver / Liver - metabolism / Liver diseases / Male / Mass spectrometry / Mass spectroscopy / Metabolism / Metabolites / Mice / Nutrition / Oxidation / Parenteral feeding / Parenteral nutrition / Parenteral Nutrition - adverse effects / Parenteral Nutrition - methods / Parenteral therapy / Soybean / Soybean Oil / Soybeans / Steatosis / Testing / Triglycerides / Triglycerides - metabolism / Unsaturated fatty acids