The liver is responsible for a number of major functions in lipid metabolism including:

 1. Facilitation of the digestion and absorption of lipids by the production of bile.

 2. Activesynthesis and oxidation of fatty acids and also synthesis of triacylglycerols and phospholipids.

 3. Conversion of fatty acids to ketone bodies (ketogenesis).

4. Synthesis and metabolism of plasma lipoproteins.

Hepatic VLDL Secretion Is Related to Dietary & Hormonal Status

The cellular events involved in hepatic VLDL formation and secretion are shown in Figure 1. VLDL assembly requires the synthesis of apo B-100 and a source of triacylglycerol. Apo B-100 is synthesized on polyribosomes and translocated to the lumen of the endoplasmic reticulum (ER) as it is formed. As the protein enters the lumen, it is lipidated with phospholipid with the aid of the microsomal triacylglycerol transfer protein (MTP), which also facilitates the transfer of triacylglycerol across the ER membrane, and apo B–containing VLDL2 (or precursor VLDL) particles are formed. The triacylglycerol is derived from lipolysis of cytosolic triacylglycerol lipid drop lets (this pool of triacylglycerol is formed using FFA either synthesized de novoor taken up from the plasma, see later) followed by reesterification in a pathway requiring phospholipid derivatives and diacylglycerol acyl transferases. Triacylglycerol not used for VLDL1 formation is recycled to the cytosolic droplets. After assembly in the ER, VLDL2 are carried in coat protein II (COPII) vesicles to the golgi, where they fuse with triacylglycerol-rich lipid droplets to produce VLDL1. Phosphatidic acid produced by the action of phospholipase D after activation by a small GTP-binding protein called ADP-ribosylation factor-1 (ARF-1) is needed for the formation of the triacylglycerol—rich particles and/or VLDL2. Although some VLDL2 particles may be secreted without fusion, most particles which leave the cell are in the form of VLDL1. These nascent VLDL then acquire apolipoproteins C and E from HDL in the circulation to become mature VLDL.

Fig1. The assembly of very-low-density lipoprotein (VLDL) in the liver. The pathways indicated underlie the events depicted in Figure 25–2. Apo B-100 is synthesized on polyribosomes and is lipidated with PL by MTP as it enters the ER lumen. Any excess is degraded in proteasomes. TG derived from lipolysis of cytosolic lipid droplets followed by resynthesis is transferred into the ER lumen with the aid of MTP and interacts with apo B-100, forming VLDL2. Excess TG is recycled to the cytosolic lipid droplets. VLDL2 are translocated to the golgi in COPII vesicles where they fuse with TG-rich particles to form VLDL1. PA is produced by activation of PLD by ARF-1 and is incorporated into the TG-rich VLDL1 and/or VLDL2. Both VLDL1 and VLDL2 may be secreted into the blood. Insulin inhibits VLDL secretion by inhibiting apo B-100 synthesis and the formation of VLDL1 from VLDL2. (Apo, apolipoprotein; ARF-1, ADP-ribosylation factor-1; FFA, free fatty acids; HDL, high-density lipoproteins; MTP, microsomal triacylglycerol transfer protein; PA, phosphatidic acid; PL, phospholipid; PLD, phospholipase D; TG, triacylglycerol.)

Triacylglycerol for VLDL formation is synthesized from FFA. The fatty acids used are derived from two possible sources: (1) de novo synthesis within the liver from acetyl-CoA derived mainly from carbohydrate (perhaps not so important in humans) and (2) uptake of FFA from the circulation. The first source is predominant in the well-fed condition, when fatty acid synthesis is high and the level of circulating FFAs is low. As triacylglycerol does not normally accumulate in the liver in these conditions, it must be inferred that it is transported from the liver in VLDL as rapidly as it is synthesized. FFAs from the circulation are the main source during starvation, the feeding of high-fat diets, or in diabetes mellitus, when hepatic lipogenesis is inhibited. Factors that enhance both the synthesis of triacyl glycerol and the secretion of VLDL by the liver include (1) the fed state rather than the starved state; (2) the feeding of diets high in carbohydrate (particularly if they contain sucrose or fructose), leading to high rates of lipogenesis and esterification of fatty acids; (3) high levels of circulating FFA; (4) ingestion of ethanol; and (5) the presence of high concentrations of insulin and low concentrations of glucagon, which enhance fatty acid synthesis and esterification and inhibit their oxidation.

Insulin suppresses hepatic VLDL secretion by inhibiting both apo B-100 synthesis and the conversion of the smaller VLDL2 into VLDL1 by fusion with bulk triacylglycerol. Some other factors which are known to inhibit or prevent VLDL assembly in the liver include the antibiotic brefeldin A, which inhibits the action of ARF-1; the sulfonylurea hypoglycemic drug, tolbutamide, dietary ω3 fatty acids, and orotic acid, an intermediate in the synthesis of pyrimidines, all of which decrease the rate of triacyl glycerol lipolysis; and a defect in the MTP gene, which lowers MTP levels. The regulation of VLDL formation in the liver is complex and involves interactions between hormonal and dietary factors that are not yet fully understood.

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مواضيع ذات صلة

Brown Adipose Tissue Promotes Thermogenesis

Hormones Regulate Fat Mobilization

Adipose Tissue is The Main Store of Triacylglycerol in The Body

Classification of Proteins

Precipitation Reactions of Proteins

Study of Protein Structure

Imbalance in the Rate of Triacylglycerol Formation & Export Causes Fatty Liver

HDL Takes Part in Both Lipoprotein Triacylglycerol & Cholesterol Metabolism

Tertiary Structure of Proteins

Secondary Structure of Proteins

Primary Structure of Proteins

Chylomicrons & Very-low Density Lipoproteins are Rapidly Catabolized