VLDL secretion

A more detailed account of the factors controlling hepatic VLDL secretion is given below. 

Hepatic VLDL Secretion Is Related to Dietary Hormonal Status... 

GN169 Gruffat-Mouty, D., B. Graulet, D. Durand, M. E. Samson-Bouma, and D. Bauchart. Effects of dietary coconut oil on apolipoprotein B synthesis and VLDL secretion by calf liver slices. Br JNutr 2001 86(1) 13-19. 

Primary increases of VLDL also reflect a genetic predisposition and are worsened by factors that increase the rate of VLDL secretion from liver, ie, obesity, alcohol, diabetes, and estrogens. Treatment includes addressing these issues and the use of fibrates or niacin as needed. Marine omega-3 fatty acids are a valuable adjuvant. 

Decreases catabolism of apo AI treduces VLDL secretion from liver Increases HDL decreases lipoprotein(a) [Lp(a)], LDL, and triglycerides Low HDL elevated VLDL, LDL, Lp(a) Oral large doses Toxicity Gastric irritation, flushing, low incidence of hepatic toxicity may reduce glucose tolerance... 

Alcohol-related liver diseases are complex, and ethanol has been shown to interact with a large number of molecular targets. Ethanol can interfere with hepatic lipid metabolism in a number of ways and is known to induce both inflammation and necrosis in the liver. Ethanol increases the formation of superoxide by Kupffer cells thus implicating oxidative stress in ethanol-induced liver disease. Similarly prooxidants (reactive oxygen species) are produced in the hepatocytes by partial reactions in the action of CYP2E1, an ethanol-induced CYP isoform. The formation of protein adducts in the microtubules by acetaldehyde, the metabolic product formed from ethanol by alcohol dehydrogenase, plays a role in the impairment of VLDL secretion associated with ethanol. 

In kindreds with this disorder, individuals may have elevated levels of VLDL, LDL, or both, and the pattern may change with time. Familial combined hyperlipoproteinemia involves an approximate doubling in VLDL secretion. It seems to be transmitted as a semidominant trait. Triglycerides can be increased by the factors noted above. Elevations of cholesterol and triglycerides are generally moderate, and xanthomas are usually absent. Drug treatment is warranted because the risk of coronary atherosclerosis is increased and diet alone does not normalize lipid levels. A reductase inhibitor or ezetimibe in combination with niacin is usually required to treat these patients. 

CM and VLDL secreted by intestinal cells and VLDL synthesized and secreted in the liver have similar metabolic fates. After secretion into the blood, newly formed CM and VLDL take up apoprotein (apo-C) from HDL and are subsequently removed from the blood (plasma half-life of less than 1 h in humans [137]) primarily by the action of lipoprotein lipase (LPL). Lipoprotein lipase is situated mainly in the vascular bed of the heart, skeletal muscle, and adipose tissue and catalyzes the breakdown of core TG to monoglycerides and free fatty acids, which are taken up into adjacent cells or recirculated in blood bound to albumin. The activity of LPL in the heart and skeletal muscle is inversely correlated with its activity in adipose tissue and is regulated by various hormones. Thus, in the fasted state, TG in CM and VLDL is preferentially delivered to the heart and skeletal muscle under the influence of adrenaline and glucagon, whereas in the fed state, insulin enhances LPL activity in adipose tissue, resulting in preferential uptake of TG into adipose tissue for storage as fat. 

Nicotinic acid inhibits hepatic triglyceride production and VLDL secretion, which lowers the plasma level of LDL and increases HDL. Nicotinic acid is mostly used to treat elevated LDL and VLDL by decreasing VLDL synthesis. 

Nicotinic acid. This reduces the plasma levels of both VLDLs and LDLs by inhibiting hepatic VLDL secretion, as well as suppressing the flux of free-fatty-acid release from adipose tissue by inhibiting lipolysis. Because of its ability to cause large reductions in circulating levels of cholesterol, nicotinic acid is used to treat Type 11, HI, IV and V hyperlipopro-teinaemias. 

Although synthesis of apoprotein B-lOO is necessary for VLDL secretion, addition of carbohydrate moieties in the Golgi apparatus does not appear to be required, since blockage of this function by tunicamycin does not reduce VLDL secretion. 

The amount of VLDL secreted by the liver is extremely variable and can be affected in a number of ways. A primary determinant of VLDL output is the flux of free fatty acids entering the liver. The liver responds to an increase in free fatty acids by synthesis of more and larger VLDLs. If saturated fatty acids predominate in the formation of triacylglycerol, the VLDL particles will be more numerous but smaller than if polyunsaturated fatty acids predominate. This finding may be related to the reduction in plasma cholesterol levels that results from elevating the proportion of polyunsaturated fats in the diet. The surface-to-volume ratio is smaller in the larger VLDLs. Since cholesterol... 

The fibric acid derivatives clofibrate and gemfibrozil (Figure 20-12) promote rapid turnover of VLDL by activating lipoprotein lipase. Gemfibrozil also inhibits VLDL secretion. Use of fibric acids may result in a modest elevation of plasma HDL cholesterol in hypertriacylglycerolemic subjects. Occasional side... 

Niacin is a vitamin that is used in high doses to treat hypercholesterolemia. Niacin acts to decrease VLDL and LDL plasma levels. Its mechanism of action is not clearly nnderstood but probably involves inhibition of VLDL secretion, which in tnm decreases the production of LDL. Niacin inhibits the release of free fatty acids from adipose tissue which leads to a decrease of free fatty acids entering the liver and decreased VLDL synthesis in the liver. This decreases the availability of VLDL for conversion to LDL (containing cholesterol esters). Niacin also increases high-density lipoprotein (HDL) (the good cholesterol ) by an nnknown mechanism. 

If there is a connection between female sex hormone levels and VLDL secretion, injection of estrogen into a male rat should have the following effects There should be a timely and measurable increase in VLDL secretion. This process requires a concomitant increase in the synthesis of the components of VLDL, that is apoproteins, triacylglycerols, phospholipid, and cholesterol. FABP synthesis should increase in response to the increased intracellular fatty acid concentrations. 

For example, VLDL secreted from hepatocytes is converted into IDL and eventually into LDL, which can then deliver its cholesterol to cells through LDL receptors (Figure... 

IV Familial hypertriglyc eridemia Increased VLDL levels Increased VLDL secretion... 

Woifrum, C., and Stoffel, M. Coactivation of Foxa2 through Pgc-lbeta promotes liver fatty acid oxidation and triglyceride/VLDL secretion. Ceil Metab 3 (2006) 99-110. 

Metabolic regulation of VLDL secretion overproduction in insulin-resistant states. 525... 

Hepatoma cell lines, such as human HepG2 hepatoma cells and McArdle 7777 rat hepatoma cells, are frequently used for studying VLDL secretion. In addition, primary hepatocytes isolated from livers of rats, mice, or hamsters are commonly used. Each model has advantages and limitations. Hepatoma cells are convenient laboratory models since they can be... 

VLDL secretion can also be studied in vivo by injection of mice or rats with the detergent Triton WR1339 or poloxmer. These compounds block the lipolysis of TG-rich lipoproteins in plasma so that the amount of plasma apo B-containing lipoproteins reflects only the secretion of apo B, in the absence of lipolysis. This methodology has some limitations, primarily because neither detergent is specific for blocking VLDL lipolysis (J.T. Billheimer, 2005). 

Sterol-response element-binding proteins (SREBPs) are transcription factors that coor-dinately increase the synthesis of fatty acids and cholesterol (Chapters 6, 7, and 14). The transcriptionally active forms of SREBPs are generated from precursor proteins by a sterol-dependent proteolytic cleavage [8]. Several studies have indicated that an increased production of transcriptionally active SREBPs stimulates VLDL secretion. 

Phosphatidylcholine is the major phospholipid on the surface monolayer of all lipoproteins, including VLDLs. In the liver, phosphatidylcholine is synthesized by two biosynthetic pathways the CDP-choline pathway and the phosphatidylethanolamine A -methyltransferase pathway (Chapter 8). Choline is an essential biosynthetic precursor of phosphatidylcholine via the CDP-choline pathway. When cells or animals are deprived of choline, plasma levels of TG and apo B are markedly reduced and TG accumulates in the liver, resulting in fatty liver. These observations led to the widely held view that the fatty liver caused by choline deficiency is due to inhibition of PC synthesis, which in turn would decrease VLDL secretion. This hypothesis was tested in primary rat hepatocytes cultured in medium lacking choline. Upon removal of choline/methionine from culture medium, the TG content of hepatocytes was increased 6-fold, and the secretion of TG and apo B in VLDL was markedly reduced. The interpretation of these experiments was that hepatic VLDL secretion requires the synthesis of phosphatidylcholine from either the CDP-choline or methylation pathways which require choline or methionine, respectively, as precursors (D.E. Vance, 1988). However, since choline deprivation was induced in a background of methionine insufficiency, it was not clear whether the lack of choline per se, and inhibition of the choline pathway for phosphatidylcholine synthesis, decreased VLDL secretion. More recent experiments have shown, surprisingly, that deficiency of choline in primary mouse hepatocytes does not reduce, but increases, phosphatidylcholine synthesis via the CDP-choline pathway, and does not decrease VLDL secretion (J.E. Vance, 2004). Thus, a deficiency of dietary choline reduces plasma TG and apo B levels by a mechanism that does not involve reduction of phosphatidylcholine synthesis. 

To determine the role of the CDP-choline pathway of phosphatidylcholine synthesis for VLDL secretion, knockout mice were generated in which the gene encoding CTP phos-phocholine cytidylyltransferase-a (Pcytla), a key enzyme in phosphatidylcholine synthesis via the CDP-choline pathway (Chapter 8), was disrupted only in the liver. TG accumulated in livers of these mice and the secretion of TG and apo B was decreased (D.E. Vance, 2004). Thus, elimination of the CDP-choline pathway in the liver inhibits VLDL secretion. In addition, disruption of the gene encoding the liver-specific enzyme, phosphatidylethanolamine V-methyltransferase, in mice fed a high-fat/high-cholesterol diet, also markedly reduces the secretion of TG and apo B in VLDLs (D.E. Vance, 2003). Thus, the hepatic synthesis of phosphatidylcholine via both the CDP-choline and methylation pathways appears to be required for normal VLDL secretion. 

There are conflicting data on whether the availability of cholesterol and/or cholesteryl esters directly influences apo B secretion. Several studies have suggested that cholesterol supply can regulate VLDL secretion. For example, VLDL production in animals and man is decreased by statin treatment, and inhibition of cholesterol synthesis by a statin, an inhibitor of the rate-limiting step of cholesterol biosynthesis (Chapter 14), reduced VLDL secretion in perfused rat livers (M. Heimberg, 1990) and primary hepatocytes. However, this effect of statins can perhaps be ascribed to increased expression of LDL receptors rather than to a reduction in cholesterol synthesis (Section 7.1). Depletion of cholesterol in rodent hepatocytes by the ABCAl-dependent lipidation of apo A1 (Chapter 19) also decreases VLDL secretion (R. Lehner, 2004). Furthermore, the secretion of apo BlOO-containing VLDLs is increased in primary hepatocytes derived from Niemann-Pick Cl-deficient mice. Niemann-Pick Cl-deficiency causes a severe defect in trafficking of unesterified cholesterol out of the lysosomal/endosomal pathway and consequently, Niemann-Pick Cl-deficient hepatocytes accumulate 5- to 10-fold more unesterified cholesterol than do wild-type hepatocytes. In hepatocytes from Niemann-Pick Cl-deficient mice, cholesterol synthesis is increased and the rate of cholesterol esterification and the amount of the transcriptionally active form of SREBP-1 are also increased (J.E. Vance, 2007). However, because of multiple alterations in lipid metabolism in these hepatocytes, increased VLDL secretion cannot be attributed specifically to increased synthesis of cholesterol or cholesteryl esters. 

Cholesteryl esters are quantitatively minor constituents (5-15% of total lipids) of VLDLs but the amount of cholesteryl esters relative to TG in VLDLs increases when rats are fed a high cholesterol diet. The esterification of cholesterol is mediated by two distinct acyl-CoA cholesterol acyltransferases (ACATs) [11]. Inhibition of cholesterol esterification with an ACAT inhibitor in hepatocytes decreased apo B secretion in some studies but not in others. For example, severe reduction in cholesteryl ester content of hepatoma cells decreased apo B secretion, whereas increased cholesteryl ester content did not stimulate apo B secretion. In mouse liver and intestine, the majority of cholesteryl esters are made by ACAT2. Nevertheless, normal quantities of apo B-containing lipoproteins are produced in mice lacking ACAT2 despite the absence of essentially all hepatic ACAT activity. However, ACAT2-deficient mice exhibit reduced intestinal absorption of cholesterol and are resistant to diet-induced hypercholesterolemia (R.V. Farese, 2(X)0). Thus, the observed reduction of plasma cholesterol in response to ACAT inhibitors is probably due to decreased cholesterol absorption rather than decreased VLDL secretion. 

Specific inhibitors of the lipid transfer activity of MTP have been developed as a potential treatment for atherosclerosis based on the premise that inhibition of MTP reduces VLDL secretion. Indeed, MTP inhibitors effectively reduce plasma cholesterol levels by up to 80% in rats, hamsters, and rabbits [13]. However, heterozygosity for MTP deficiency in humans does not diminish plasma lipids or lipoproteins, indicating that a modest reduction in MTP activity does not limit VLDL production. On the other hand, adenovirus-mediated over-expression of MTP in mouse liver increased the secretion, and plasma levels, of TG, apo B100, and apo B48 (D.J. Rader, 1999). MTP inhibitors are not currently used therapeutically, probably because they induce some storage of TG in the liver (steatosis) as a result of the blockage in VLDL secretion. 

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