*Non-Alcoholic Fatty Liver Disease: Pathogenesis and the Significance of High-Density… DOI: http://dx.doi.org/10.5772/intechopen.108199*

hydrolysed by the pancreatic and intestinal lipases. Hydrolysis products, such as free fatty acids and monoglycerides are then transferred to the intestinal epithelial cell, where they diffuse through the epithelial cell membranes into the intestinal mucosal cells. In the small intestinal mucosal cells, free fatty acids and monoglycerides reassemble to form triglycerides, which then combine with proteins, phospholipids, free and esterified cholesterol to form Chylomicrons [29]. Chylomicrons are the lipoprotein class responsible for dietary lipids transport. After their formation in the enterocytes, chylomicrons, which mainly contain triglycerides, are secreted into the lacteals and enter into the blood circulation through the lymphatic system. Chylomicrons contain apolipoproteins (Apos) B-48, C-II, and E. The Apo C-II is an essential co-factor of lipoprotein lipase (LPL) during the transportation of fatty acids to adipose tissue. After LPL activity, the chylomicron remnant is relatively enriched in cholesterol due to the loss of triacylglycerol and absorbed into the liver by Apo E [30]. Lipoprotein, which is exposed on the chylomicron surface, activates the lipoprotein lipase attached to the capillary beds in adipose and skeletal muscle tissues, which then hydrolyses triglycerides into free fatty acids (FFAs) and glycerol. The FFAs enter the muscle cells, where they are used for energy production and to the adipocytes, where they would be re-esterified into triglycerides for storage. The chylomicron remnants return to HDL to be recycled by the liver and are recognized by specific hepatic receptors that rapidly remove them from the circulation by endocytosis. The cholesterol found in chylomicron remnants can be used for VLDL, bile acid formation, or stored as cholesteryl esters [28]. While the chylomicrons are responsible for the transport of dietary lipids, endogenously synthesized triglycerides, cholesterols and cholesteryl esters, including VLDL, LDL and HDL are mainly involved in the endogenous lipid metabolism pathway. The endogenous pathway starts with the synthesis of VLDL particles, which are triglyceride-rich and contain Apo B-100, C-II, and E. After the removal of the triglycerides in adipose tissue, a portion of VLDL remnants is metabolized to LDL particles [30]. Thus, VLDL remnants are either removed from the circulation by the liver or undergo further transformation by lipoprotein lipase or hepatic lipase to form LDL. As LPL cleaves TGs, the cholesterol concentration within the lipoprotein increases and becomes a smaller denser lipoprotein named "intermediate-density lipoproteins" (IDL) [27]. The IDL can be taken up by the liver through an apoE-dependent process, while LDL is taken up by the liver through the binding of apoB100 to LDL receptors. The LDL which mainly contains cholesteryl esters and phospholipids circulates in the blood and binds to specific receptors that are widely distributed throughout the tissues. The small VLDL, IDL, and LDL particles may be taken up by peripheral tissues to deliver nutrients, cholesterol, and fat-soluble vitamins, to be used for the synthesis of steroid hormones and cell membranes as well as for hepatic metabolism [31].

HDL is a mixture of lipoproteins associated with various minor lipids and proteins that stimulates the function of HDL. Most of the HDL particles arise from lipid-free or poorly lipidated apoA-I secreted by hepatocytes and the intestinal mucosa or dissociated from lipolyzed chylomicrons and VLDL as well as from interconverting mature HDL particles [32]. The interaction between the lipid-free or poorly lipidated apoA-I, also known as the pre-β1-HDL with the ATP-binding cassette transporter A1 (ABCA1) leads to efflux of phospholipids and unesterified cholesterol from various cells, such as hepatocytes, enterocytes, and macrophages, which progress to the formation of small discoidal HDL particles, known as α4-HDL. The α4-HDL precursors can further facilitate the lipid efflux from cells, basically from scavenger receptor BI (SR-BI) or ATP-binding cassette transporter G1 (ABCG1) [2]. The effluxed cholesterol and phosphatidylcholine function as substrates of lecithin-cholesterol acyltransferase (LCAT) to generate water-insoluble cholesteryl esters, which transform to the core mature spherical HDL. The initial small α-HDL3 particles develop into larger α-HDL2 particles obtained from phospholipids and cholesterol from both cells (SR-BI or ABCG1), which is involved with the activity of phospholipid transfer protein, and apoB-containing lipoproteins fused with other HDL particles. The breaking down of HDL varies from that of LDL since only a minor proportion of HDL would be removed by holo-particle uptake into cells. In this poorly understood pathway, a high-affinity interaction of apoA-I with ectopic F0F1–ATPase leads to the generation of ADP, which stimulates purinergic receptors to facilitate the uptake of HDL by an as-yet-unidentified low-affinity HDL receptor [2, 32]. These pathways (**Figure 3**) promote the elimination of lipids from HDL irrespective of their protein content. The cholesteryl ester transfer protein (CETP) converts triglycerides of apoB-containing lipoproteins for cholesteryl esters of HDL, which are finally removed through the LDL receptor pathway, while SR-BI coordinates the uptake of HDL lipids into the liver and steroidogenic organs [8]. The elimination of cholesteryl esters by CETP and SR-BI, and the lipolysis of triglycerides and phospholipids by hepatic lipase and endothelial lipase, respectively, promote the transformation of HDL2 to HDL3, and the ultimate formation of pre-β1-HDL. This lipid-poor apoA-I either transforms to a mature HDL by activating ABCA1-mediated lipid efflux from several cells or is filtrated by the renal glomeruli through the proximal tubule of the kidneys. The apoA-I is endocytosed by the cubilin and megalin receptors and targeted for lysosomal degradation [32].
