Altered liver expression of Rev-Erba-associated transcription factors and liver hypoxia might be the link between cardiovascular disease and liver injury

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

Cold Spring Harbor, New York

Simposio; 76th Symposium: Metabolism & Disease; 2011

Cold Spring Harbor Lboratory

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 liver that may explain the link between NAFLD and CVD we took advantage of a rat model of CVD, the spontaneously hypertensive rat (SHR), and developed a high fat diet (HFD) induced model of NAFLD in the SHR and in the normotensive, insulin-sensitive control Wistar-Kyoto (WKY) strain. This strategy allows us to explore the events that occur in the liver when fatty deposits develop in different metabolic environments. Sixteen–week-old male SHR (n=13) and WKY (n=14) were included; the rats 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. 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). We measured the liver transcript levels of 40 genes encoding proteins involved in nuclear receptor family, apoptosis, hypoxia, grow factors, cardiovascular pathophysiology, lipid and glucose homeostasis, fatty acid metabolism, and insulin signaling. Liver abundance of Rev-Erba mRNA (p<0.04), a gene that orchestrates hepatic circadian variations in metabolic transcription clusters, along with SIRT1 (p<0.001) and PPARg (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 may predispose to an increased susceptibility of the liver to undergo pathological changes including inflammation, 3-CVD is associated with abnormal liver enzymes regardless of NAFLD, 4-Altered liver expression of Rev-Erba-associated transcription factors along with liver hypoxia might be the link between CVD and liver injury.