**1. Introduction**

The liver is the largest solid organ in the body, and plays important roles in metabolism and processing of nutrients and toxins, with cardinal functions in the gastrointestinal system and the digestion process. The liver is composed of two lobes- right and left, encapsulated by the fibrous Gleason capsule. Cells in the liver are mainly hepatocytes- composing about 60% of the liver cells, sinusoidal endothelial cells (18%), Kupffer cells (KCs 13%), hepatic stellate cells (HSCs, 4–10%), and NK cells (2%) [1–4]. Normally, hepatocytes are arranged in cords surrounding bile canaliculi which drain bile secreted from hepatocytes into bile ducts of the portal triad (**Figure 1**: normal liver).

The extracellular matrix (ECM) is a large network of proteins, glycoseaminoglycans and glycoconjugates and other molecules that surround, support and help to maintain normal structure, function, and integrity of body organs. The ECM helps cells to attach to, and communicate with adjacent cells, and plays important roles in cell growth, cell adhesion, cell movement and migration, and additional cell functions.

### **Figure 1.**

*Structure of normal liver. The liver is composed of two lobes. Hepatocytes are the main cell type in the liver, and are arranged in cords surrounding canaliculi which drain bile into bile ducts to help in digestion of nutrients in the gut. Sections of H&E stained liver slides from normal liver (upper picture) and fatty liver showing intracellular vaculations and cell ballooning (lower picture), magnified X40.*

Heparan sulfate proteoglycans (HSPG) are the main constituent of the ECM. These macromolecules are composed of glycoseaminoglycan chains covalently bound to a protein core, and are different from each other in their structure and configuration, thus performing different roles in the ECM, which are mainly either adhesive or fibrotic [5]. HSPGs are either embedded in the cell surface or located in the ECM, and play important role in cell-cell and cell-ECM communication and interaction [6–8], thus serve as mediators in both normal biologic and in pathologic processes, like cell differentiation [9, 10], cell adhesion [11], tissue repair [12, 13], tumor formation and spread [5, 10, 14, 15], autoimmune and inflammatory processes [16–18], diabetes mellitus and its complications [19], and vessel wall pathologies- like atherosclerosis [20–22]. Heparanase, an endo-β-D-glucoronidase, is the only enzyme in mammalians that cleaves HS chains in the HSPGs in several specific sites along the polysaccharide chains, thus resulting in modification of structure and function of the HSPGs [21, 23–25]. In its intracellular role, heparanase participates in degradation and turnover of membrane-associated HSPGs [26, 27]. The extracellular enzyme is involved in HSPG degradation by cleavage of the HS chains, resulting in alteration of the basal membrane and ECM structure, and thus affects the pool of HS-bound ligands, which are released into the surrounding environment. All these actions result in remodeling of the ECM network, and enable the diffusion of different cytokines, growth factors, and lipoproteins, which facilitate cell motility and result in angiogenesis, inflammation, coagulation, fibrosis, and stimulation of autophagy and exosome production [28–30].

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world, and affects up to 30% of adults [31], with increasing prevalence with age, in line with the global pandemic of obesity and type 2 diabetes mellitus. NAFLD is defined as the intracellular accumulation of fat droplets in the hepatocytes (liver steatosis), as evident by either radiologic or histologic testing, in the absence of alternative etiologies of chronic liver disease or secondary causes of liver steatosis (like the use of various drugs, prolonged alcohol consumption, or inherited or acquired several metabolic pathologies). Isolated NAFLD is characterized by liver steatosis (although could be associated with mild chronic inflammation) in at least 5% of hepatocytes [32]. Natural course of the disease is slow progression to nonalcoholic steatohepatitis (NASH), defined by a pattern of characteristic findings that include liver steatosis, lobular and portal inflammation, and injured liver cells in the form of hepatocyte ballooning. The NAFLD activity score (NAS) is used to assess the degree of hepatic steatosis, lobular inflammation, hepatocellular ballooning, and degree of liver fibrosis [32]. In advanced stages, NAFLD may progress to profound liver fibrosis- as assessed by the METAVIR scoring system, liver cirrhosis, portal hypertension, and end-stage liver diseases with related complications, including liver failure, decompensated liver cirrhosis, and even liver malignancies- like hepatocellular carcinoma (HCC) [33], making NAFLD a leading etiology for liver transplantation in the western world [34–36].
