**2.4 Heparanase inhibition and liver steatosis**

In our former studies, we investigated the effect of heparanase inhibition on hemodynamic, metabolic and histopathologic parameters of body systems in mice, mainly aortic atherosclerosis and fatty liver.

In apolipoprotein E deficient (E0) mice, inhibition of heparanase activity by two inhibitors- PG545 (PIXATIMOD), a HS mimetic with proved inhibitory effect on heparanase, caused significant reduction of serum glucose levels, blood pressure and oxidative stress in serum [79]. In another project, we have shown that the same heparanase inhibitor, used in E0 mice placed on high fat diet, significantly attenuated the development of atherosclerotic lesions in representing sections taken from the aortic arch, along significant reduction of the aortic wall thickness compared to control mice. In addition, we demonstrated in the same study that in comparison to placebo, treatment with PG545 significantly reduced blood pressure and serum levels of TC, TGs, and LDL-C, besides significant reduction of oxidative stress in serum, all of which are considered independent risk factors for the development and progression of atherosclerosis [80].

Recently, we studied the effect of two different heparanase inhibitors on the development of liver steatosis in two kinds of mice. In this study, both E0 mice and C57 Balb-c mice were placed on either chow diet or high fat diet, and treated with either PG545, SST0001- a 100% N-acetylated and glycol split non-anticoagulant heparin which exerts potent anti heparanase activity, or placebo injection (normal saline). Both heparanase inhibitors significantly attenuated the development of liver steatosis. In accordance with our former studies, also in this study serum analyses revealed significant reduction in serum levels of TC and TGs, besides lowering the mRNA expression of key factors involved lipid metabolism, including lipid uptake by the liver, lipolysis, lipogenesis, and beta-oxidation in the liver cells. These beneficial effects seem to heparanase-dependent, as inhibition of heparanase resulted in the favorable effect of attenuating the development of fatty liver [81].
