Saturated Fatty Acids Promote Endoplasmic Reticulum Stress and Liver Injury in Rats with Hepatic Steatosis

• Published in: Endocrinology (Philadelphia) 2006-02, Vol.147 (2), p.943-951
• Main Authors: Wang, Dong, Wei, Yuren, Pagliassotti, Michael J
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Apoptosis - physiology; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Biological and medical sciences; Composition; Diabetes mellitus (non-insulin dependent); Dietary Fats - metabolism; DNA-Binding Proteins; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Fatty acids; Fatty Acids - metabolism; Fatty liver; Fatty Liver - metabolism; Fatty Liver - pathology; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Hepatectomy; HSP70 Heat-Shock Proteins - metabolism; Injuries; Leptin; Lipopolysaccharides; Liver; Liver diseases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Membrane Proteins - metabolism; mRNA; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Obesity; Other diseases. Semiology; Pathogenesis; Proteins; Rats; Rats, Wistar; Regulatory Factor X Transcription Factors; RNA, Messenger - analysis; Statistics, Nonparametric; Steatosis; Transcription Factors; Triglycerides; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2005-0570

Nonalcoholic fatty liver disease is a relatively new hepatic sequela of obesity and type 2 diabetes. The pathogenesis of liver injury and disease progression in nonalcoholic fatty liver disease, however, is poorly understood. The present study examined the hypothesis that the composition of fatty acids in the steatotic liver promotes liver injury. Using dietary models of hepatic steatosis characterized by similar accumulation of total triglyceride but different composition of fatty acids, we show that hepatic steatosis characterized by increased saturated fatty acids is associated with increased liver injury and markers of endoplasmic reticulum stress (e.g. X-box binding protein-1 mRNA splicing and glucose-regulated protein 78 expression). These changes preceded and/or occurred independently of obesity and differences in leptin, TNFα, insulin action, and mitochondrial function. In addition, hepatic steatosis characterized by increased saturated fatty acids reduced proliferative capacity in response to partial hepatectomy and increased liver injury in response to lipopolysaccharide. These data suggest that the composition of fatty acids in the steatotic liver is an important determinant of susceptibility to liver injury.