INVESTIGADORES
PIROLA Carlos Jose
artículos
Título:
Cardiovascular disease is associated with high fat diet-induced liver damage and upregulation of hepatic expression of hypoxia-inducible factor 1 alpha in a rat model .
Autor/es:
BURGUENO, A.L.; FERNANDEZ GIANOTTI T; GONZALES MANSILLA N; PIROLA CJ.; SOOKOIAN S.
Revista:
CLINICAL SCIENCE (LONDON, ENGLAND : 1979)
Editorial:
PORTLAND PRESS LTD
Referencias:
Lugar: Londres; Año: 2013 vol. 124 p. 53 - 63
ISSN:
0143-5221
Resumen:
Cardiovascular disease (CVD) is associated with abnormal liver enzymes, and nonalcoholic fatty liver disease (NAFLD) is independently associated with cardiovascular risk. To gain insights into the molecular events underlying the association between liver enzymes and CVD, we developed a high-fat diet (HFD)-induced NAFLD in the spontaneously hypertensive rat (SHR) and its control Wistar-Kyoto (WKY) strain. We hypothesized that hepatic induction of hypoxia-inducible factor 1 alpha (Hif1a) might be the link between CVD and liver injury. Sixteen-week-old male SHR (n=13) and WKY (n=14) rats were divided into two experimental groups: standard chow diet and HFD (10 weeks). Results: HFD-fed rats irrespective of strain developed NAFLD; only HFD-SHR showed focus of lobular inflammation and high levels of hepatic tumor necrosis factor á. SHR rats had significantly higher liver weight, and alanine aminotransferase (ALT) levels, irrespective of NAFLD. Liver abundance of Hif1a mRNA and protein were overexpressed in SHRs (p<0.04) and significantly correlated with ALT levels (R=0.50, p<0.006); this effect was not reverted by a direct acting splanchnic vasodilator (hydralazine). Angiogenesis may be induced by HFD, but the disease model showed significantly higher hepatic vascular endothelial growth factor levels (p<0.025) even in absence of dietary insult. Hif1a mRNA overexpression was not observed in other tissues. Liver mRNA of Rev-Erba (p<0.04), Ppara (p<0.05), Pparg (p<0.001), and Sirt1 (p<0.001) was significantly upregulated in SHRs, irrespective of NAFLD; Sirt1 and Hif1a mRNAs were significantly correlated (R=0.71, p<0.00002). Conclusion: CVD is associated with Hif1a-related liver damage, hepatomegaly, and reprogramming of liver metabolism probably to compensate metabolic demands.