Altered liver expression of nuclear receptors involved in the circadian control of metabolism and upregulation of hipoxia inducible factor-alpha may be the link between cardiovascular disease and liver injury.

SOOKOIAN S; BURGUEÑO A; FERNÁNDEZ GIANOTTI T; PIROLA CJ

San Francisco

Congreso; 62nd Annual Meeting of American Association for the Study of Liver Diseases; 2011

American Association for the Study of Liver Diseases

The biologic mechanisms responsible for the association between nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) are hardly explained by the current epidemiological evidence, in part because of limitations to sample human liver tissue and the difficulties in dissecting phenotypes. To gain insights into the molecular events occurring in the liver that may explain the link between NAFLD and CVD we took advantage of a rat model of CVD and metabolic syndrome, the spontaneously hypertensive rat (SHR), and developed a high fat diet (HFD)-induced model of NAFLD in the SHR and its control normotensive, insulin-sensitive Wistar-Kyoto (WKY) strain. This experimental model allows us to explore the hypothesis that the development of fatty liver in different metabolic environments is associated with a differential transcriptional profile. Methods: Sixteen?week-old male SHR (n=13) and WKY (n=14) were randomly divided into 2 experimental groups: standard chow diet (SHR n= 7 and WKY n=7), and ad libitum access to HFD (SHR n=6 and WKT n=7), for 10 weeks. We measured the liver transcript levels of 30 genes encoding proteins belonging to the nuclear receptor family and/or involved in apoptosis, hypoxia, grow factors, cardiovascular pathophysiology, lipid, glucose and fatty acid metabolism including insulin signaling. Results: HFD-fed rats irrespective of the strain developed severe hepatic steatosis; only HFD-SHR rats showed focus of lobular inflammation. SHR rats showed significantly higher liver and heart weight, regardless of the presence of NAFLD. Liver weight significantly correlated with alkaline phosphatase levels (R=0.65, p<0.0003), HOMA-IR (R=0.50, p<1x10-5) and heart weight (R=0.76, p<1x10-5). Liver abundance of mRNA of nuclear receptors and integral components of the molecular clock machinery, such as Rev-Erba (p<0.04), a gene that orchestrates hepatic circadian variations in metabolic transcription clusters, Ppara (p<0.05), Pparg (p<0.001) and Sirt1 (p<0.001) was significantly upregulated only in SHR, irrespective of the presence of NAFLD. Similar pattern was observed for hypoxia inducible factor 1 alpha, p<0.04. In conclusion: 1-Liver seems to be a target for organ damage when CVD is present, 2-CVD is associated with abnormal liver enzymes regardless of NAFLD and then may predispose to an increased susceptibility of the liver to undergo pathological changes including inflammation, 3-Altered liver expression of nuclear receptors, probably by modulation of the circadian control of metabolism, along with liver hypoxia might be the link between CVD and liver injury.