Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 174, Issue 4, Pages 1329-1337Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2009.080697
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Funding
- National Institutes of Health [RO1-DK56345, RO1-HL073101]
- Novartis Pharmaceutical Co.
- University of Missouri Research Council
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Emerging evidence indicates that impaired mitochondrial fatty acid beta-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 beta-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 beta-oxidation. Compared with Sprague-Dawley littermates, Rent livers exhibited mitochondrial damage and reduced beta-oxidation, as evidenced by ultrastructural abnormalities, decrease of mitochondrial content, percentage of palmitate oxidation to CO2, enzymatic activities (beta-HAD and citrate synthase), and the expression levels of cytochrome c, cytochrome c oxidase subunit 1, and mitochondria) 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 beta-oxidation, contributing to liver steatosis. (Am J Pathol 2009, 174:1329-1337; DOI: 10.2353/ajpath.2009.080697)
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