Oxidative Stress-Mediated Mitochondrial Dysfunction Contributes to Angiotensin II-Induced Nonalcoholic Fatty Liver Disease in Transgenic Ren2 Rats

• Published in: The American journal of pathology Vol. 174; no. 4; pp. 1329 - 1337
• Main Authors: Wei, Yongzhong, Clark, Suzanne E, Thyfault, John P, Uptergrove, Grace M.E, Li, Wenhan, Whaley-Connell, Adam T, Ferrario, Carlos M, Sowers, James R, Ibdah, Jamal A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.04.2009; ASIP; American Society for Investigative Pathology
• Subjects: Angiotensin II - drug effects; Angiotensin II - metabolism; Animals; Antihypertensive Agents - pharmacology; Antioxidants - pharmacology; Biological and medical sciences; Blotting, Western; Cyclic N-Oxides - pharmacology; DNA, Mitochondrial - drug effects; Fatty Acids - metabolism; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty Liver - physiopathology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression - drug effects; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Microscopy, Electron, Transmission; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; Other diseases. Semiology; Oxidation-Reduction - drug effects; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Regular; Reverse Transcriptase Polymerase Chain Reaction; Spin Labels; Tetrazoles - pharmacology; Valine - analogs & derivatives; Valine - pharmacology; Valsartan; Oxidative stress; Rat; Rodentia; Hepatic disease; Renin angiotensin system; Vertebrata; Anatomic pathology; Mitochondria; Mammalia; Dysfunction; Animal; Non alcoholic steatohepatitis; Digestive diseases; Angiotensin II
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.080697

Emerging evidence indicates that impaired mitochondrial fatty acid β-oxidation plays a key role in liver steatosis. We have recently demonstrated that increased angiotensin (ANG) II causes progressive hepatic steatosis associated with oxidative stress; however, the underlying mechanisms remain unclear. We hypothesized that ANG II causes hepatic mitochondrial oxidative damage and impairs mitochondrial β-oxidation, thereby leading to hepatic steatosis. We used the Ren2 rat with elevated endogenous ANG II levels to evaluate mitochondrial ultrastructural changes, gene expression levels, and β-oxidation. Compared with Sprague-Dawley littermates, Ren2 livers exhibited mitochondrial damage and reduced β-oxidation, as evidenced by ultrastructural abnormalities, decrease of mitochondrial content, percentage of palmitate oxidation to CO2 , enzymatic activities (β-HAD and citrate synthase), and the expression levels of cytochrome c , cytochrome c oxidase subunit 1, and mitochondrial transcription factor A. These abnormalities were improved with either ANG II receptor blocker valsartan or superoxide dismutase/catalase mimetic tempol treatment. Both valsartan and tempol substantially attenuated mitochondrial lipid peroxidation in Ren2 livers. Interestingly, there was no difference in the expression of key enzymes (ACC1 and FAS) for fatty acid syntheses and their transcription factors (SREBP-1c and ChREBP) between Sprague-Dawley, untreated Ren2, and valsartan- or tempol-treated Ren2 rats. These results document that ANG II induces mitochondrial oxidative damage and impairs mitochondrial β-oxidation, contributing to liver steatosis.