Liver-specific deletion of the corepressor GPS2 alleviates atherosclerosis and dyslipidemia

Atherosclerosis is a chronic inflammatory disease and a major cause of cardiovascular disease (CVD). The chronic inflammation resulting from the interaction between modified lipoproteins, monocyte-derived macrophages, T cells, and the normal cellular elements of the arterial wall leadsto the development of atherosclerotic lesionsthat protrude into the arterial lumen. Atherosclerosis is a dynamic disorder,and it is not possible to consider the disease as an independent process, unaffected by other systemsin the body. Several tasks performed by the liver, including lipid metabolism, and inflammatory liver disorders have been implicated in the pathogenesis of atherosclerosis. Non-alcoholic fatty liver disease (NAFLD) has been linked with insulin resistance,obesity, and metabolic syndrome, conditions known to be associated with CVD and subclinical atherosclerosis. Our previous work showed that hepatocyte-specific GPS2 knock out in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genesby the de-repression of PPARαnuclear receptor. Taking all thisinto account, we generated and characterized liver-specific GPS2 KO mice in the ApoE KO background (ApoE-LKO) to analysehow liver GPS2 pathways affect atherogenesis. After 12 weeks on an atherogenic diet, ApoE-LKO mice showed smaller atherosclerotic lesion areasin the aortic root. Their body and epididymal fat pad weights were lower, exhibited less atherogenic lipoproteinprofile (lower cholesterol and triglycerides levelswith enrichment in HDL fractions), and liver total cholesterol content was significantly reducedcomparedto their ApoEKO littermates.In addition, the expression of inflammatory genes was reduced in theliver,along with changes in hepatic lipid metabolism gene expression signature.Interestingly, the expression of fibroblast growth factor 21 (FGF21), a target of PPARα, was significantly increased, as well asthe circulating FGF21 levels. In animal studies, FGF21 hasbeen shown toreduceatherosclerosis,and in humanclinical trials,FGF21 pharmacological treatment has shown to improvethe cardiometabolic profile in obese patients with type 2 diabetes. Our preliminary data using shRNAs against FGF21 seems to corroborate the positive effect of FGF21 induction in ApoELKO mice. Collectively, our study reveals that the absence in the liver of the corepressor GPS2 improves atherosclerosis development and alleviates dyslipidemia, probably in part by the induction of FGF21.