Nitro-fatty acids protect against steatosis and fibrosis during development of nonalcoholic fatty liver disease in mice

• Published in: EBioMedicine Vol. 41; pp. 62 - 72
• Main Authors: Rom, Oren, Xu, Guan, Guo, Yanhong, Zhu, Yunhao, Wang, Huilun, Zhang, Jifeng, Fan, Yanbo, Liang, Wenying, Lu, Haocheng, Liu, Yuhao, Aviram, Michael, Liu, Zhipeng, Kim, Seongho, Liu, Wanqing, Wang, Xueding, Chen, Y. Eugene, Villacorta, Luis
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2019; Elsevier
• Subjects: Animals; Energy Metabolism; Lipogenesis; Liver - diagnostic imaging; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Nitro-fatty acids; Non-alcoholic fatty liver disease; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Steatohepatitis; Non-invasive liver imaging, liver fibrosis; Oleic Acids - administration & dosage; Oleic Acids - pharmacology; Oleic Acids - therapeutic use; Proteolysis; Research paper; Sterol Regulatory Element Binding Protein 1 - metabolism; Triglycerides - metabolism; Non-alcoholic Steatohepatitis; Nitro-fatty acids; Non-alcoholic fatty liver disease; Non-invasive liver imaging, liver fibrosis
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2019.02.019

Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are reaching global epidemic proportions. Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment and a reversal of NASH progression and/or regression of the disease. Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO2 to treat advanced NAFLD was tested herein in a model of long-term NASH diet-induced liver damage. Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental model of NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental therapy with OA-NO2. Experimental controls included equimolar amounts of the non-nitrated oleic acid (OA). CLAMS and NMR-based analysis was used for energy metabolism. CLAMS and NMR-based analysis demonstrates that OA-NO2 improves body composition and energy metabolism and inhibits hepatic triglyceride (TG) accumulation. Photoacoustic-ultrasound imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO2. RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1 proteolytic activation and subsequent lipogenesis gene expression by OA-NO2. These results were further supported by histological analysis and quantification of lipid accumulation, lobular inflammation (F4/80 staining) and fibrosis (collagen deposition, αSMA staining) as well as established parameters of liver damage (ALT). In vitro studies indicate that OA-NO2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells. OA-NO2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation.