**1.1 Normal lipid uptake by the liver cells**

Upon food intake, lipid particles in the form of triglycerides (TGs)- the main form of lipids in the food, free cholesterol, and cholesterol ester, undergo emulsification into small lipid particles by bile, and are then hydrolyzed into free fatty acids (FFAs) and monoglycerides by the pancreatic lipase in the small intestine, where these small particles undergo absorption into the blood circulation. After absorption by the intestinal cells, together with phospholipids, cholesterol and proteins, the small lipid particles form chylomicrons that enter the blood from the lymphatic system. The liver is the main organ in the body in which lipid metabolism occurs, and in the liver cells occur processes of lipid digestion, absorption, synthesis, decomposition, and transport.

Most of the lipids in the body are stored in the form of TGs in adipose tissue. FFAs are the main constituents in TGs in body fat, from which they can be dissolved under different circumstances and enter the blood. For being transported in the blood circulation, FFAs bind to albumin, while cholesterol binds to globulin to form lipoproteins, which may contain more TGs in the form of low density lipoprotein cholesterol (LDL-c), or less TGs forming high density lipoprotein cholesterol (HDL-c), and according to the density of the lipoproteins, plasma lipoproteins are divided into four subgroups: chylomicrons, very low density lipoprotein (v-LDL),

## **Figure 2.**

*Schematic presentation of membrane associated structures involved in lipid uptake and metabolism in the liver. Lipid particles ingested in the intestine/formed by lipolysis from fat tissue enter blood circulation, and undergo uptake into hepatocytes utilizing different transmembrane structures, including the low density lipoprotein receptor (LDLR), LDL receptor-related protein (LRP), CD36 and direct endocytosis by heparan sulfate proteoglycanes (HSPGs). Inside the hepatocytes, lipid particles undergo β-oxidation in intra-cellular organelles. HSPGs play rol in lipid uptake and metabolism by hepatocytes. Focus is given to sites where heparanase is active in processing of lipid particles, as well as sites where heparanase inhibition may occur and cause decreased lipid uptake by the hepatocytes. Hpa = Heparanase. LDL-c = low density lipoprotein cholesterol, HDL-c = high density lipoprotein choleterol, HS = heparan sulfate.*

LDL, and HDL. Upon binding to lipids, proteins take part in transporting lipids in the plasma, together forming the apolipoproteins (**Figure 2**).

While the main source of fat in the body comes from food ingestion, the body can utilize endogenous fat which is stored mainly in the adipose tissue. In different circumstances, fat in the adipose cells may undergo hydrolyzation into glycerol and FFAs by the enzyme lipase. Upon hydrolysis, glycerol and FFAs are released into the blood and can be used as a source of energy or ingested by the liver cells. HSPGs play important role in lipid uptake by hepatocytes, mainly following removal of the attached lipoprotein particles [37, 38].
