Comparative transcriptomic and metabolomic analysis of fenofibrate and fish oil treatments in mice

Abstract

Elevated circulating triglycerides, which are considered a risk factor for cardiovascular disease, can be targeted by treatment with fenofibrate or fish oil. To gain insight into underlying mechanisms, we carried out a comparative transcriptomics and metabolomics analysis of the effect of 2 wk treatment with fenofibrate and fish oil in mice. Plasma triglycerides were significantly decreased by fenofibrate (-49.1%) and fish oil (-21.8%), whereas plasma cholesterol was increased by fenofibrate (+29.9%) and decreased by fish oil (-32.8%). Levels of various phospholipid species were specifically decreased by fish oil, while levels of Krebs cycle intermediates were increased specifically by fenofibrate. Plasma levels of many amino acids were altered by fenofibrate and to a lesser extent by fish oil. Both fenofibrate and fish oil upregulated genes involved in fatty acid metabolism and downregulated genes involved in blood coagulation and fibrinolysis. Significant overlap in gene regulation by fenofibrate and fish oil was observed, reflecting their property as high or low affinity agonist for peroxisome proliferator-activated receptor-α, respectively. Fenofibrate specifically downregulated genes involved in complement cascade and inflammatory response. Fish oil specifically downregulated genes involved in cholesterol and fatty acid biosynthesis and upregulated genes involved in amino acid and arachidonic acid metabolism. Taken together, the data indicate that despite being similarly potent toward modulating plasma free fatty acids, cholesterol, and triglyceride levels, fish oil causes modest changes in gene expression likely via activation of multiple mechanistic pathways, whereas fenofibrate causes pronounced gene expression changes via a single pathway, reflecting the key difference between nutritional and pharmacological intervention.

PPARα-independent actions of omega-3 PUFAs contribute to their beneficial effects on adiposity and glucose homeostasis

“…Importantly, these effects of n-3 PUFAs have been shown to be independent of PPARα, as the suppression of SREBP1 and lipogenic gene expression by FO still occurs in liver of PPARα knockout mice4041. In contrast to the effects of FO, other studies have reported that pharmacological PPARα activation promotes the expression of lipogenic enzymes434445, and the findings of the current study, as well as those in a recent report comparing the PPARα agonist fenofibrate and FO, demonstrate that n-3 PUFA and PPARα activating compounds have opposing effects on a number of biosynthetic pathways, including FA synthesis46. Thus the lipid-lowering effect of FO in liver is not solely due to acceleration of fatty acid oxidation by PPARα activation and is likely also due to the influence of n-3 PUFAs on other signalling pathways.…”

Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α

“…Extensive gene-array profiling of the effects of the PPARα agonist ciprofibrate in the cynomolgus monkey showed the expected upregulation of fatty acid oxidation and mitochondrial oxidative phosphorylation, but also the strong downregulation of many targets in the complement and coagulation cascade [39] . The comple- 207 ment and coagulation cascade was also among the strongest negative targets of fenofibrate in mice [40] , and was also repressed by clofibrate, Wy-14,643 and gemfibrozil in rats [41] . Bile acid signaling and coagulation seem quite unrelated.…”

Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

“…A better understanding of PPARa regulation by different nutritional signals in healthy individuals and in MetS patients will allow the design of specific pharmacological therapies, simultaneously targeting different NASHtriggering factors. Moreover, to improve NASH, dietary strategies, such as n-3 PUFA supplementation may be considered to ameliorate steatosis and inflammation, by a mechanism that may partially rely on PPARa activation [148,149]. However, the efficacy of n-3 PUFA in the treatment of NASH in human subjects remains to be demonstrated.…”