Liver cells lipid metabolism

Changes in cell lipid metabolism were also used to address specific diseases of the liver. As the metabolic change produced in hepatic cells by hepatitis C virus (HC V) is characterized by accumulation of lipid droplets. Nan et al. [31] used a combination of CARS and two-photon excitation fluorescence (TEPF) microscopies to simultaneously examine the subcellular localization of HCV RNA and changes in Upid phenotype of hepatoma cells. Lyn et al. [32] used TPF and CARS microscopies to demonstrate the coimection among the dispersion of HCV RNA from repUcation sites, change in lipid storage, and increase in lipid droplet size. 

Palytoxin is hemolytic (4) and is an extremely potent toxin (7). We have shown that in rat liver cells palytoxin stimulates de-esterification of cellular lipids to liberate arachidonic acid (5). These rat liver cells metabolize this increased arachidonic acid via the cyclooxygenase pathway to produce prostaglandin (PG) I2 and lesser amounts of PGE2 and PGp2. Palytoxin acts on many cells in culture to stimulate the production of cyclooxygenase metabolites (Table I). Clearly, the myriad pharmacological effects of the arachidonic acid metabolites must be considered in any explanation of the many clinical manifestations of palytoxin s toxicity. 

On the other hand, microsomes may also directly oxidize or reduce various substrates. As already mentioned, microsomal oxidation of carbon tetrachloride results in the formation of trichloromethyl free radical and the initiation of lipid peroxidation. The effect of carbon tetrachloride on microsomes has been widely studied in connection with its cytotoxic activity in humans and animals. It has been shown that CCI4 is reduced by cytochrome P-450. For example, by the use of spin-trapping technique, Albani et al. [38] demonstrated the formation of the CCI3 radical in rat liver microsomal fractions and in vivo in rats. McCay et al. [39] found that carbon tetrachloride metabolism to CC13 by rat liver accompanied by the formation of lipid dienyl and lipid peroxydienyl radicals. The incubation of carbon tetrachloride with liver cells resulted in the formation of the C02 free radical (identified as the PBN-CO2 radical spin adduct) in addition to trichoromethyl radical [40]. It was found that glutathione rather than dioxygen is needed for the formation of this additional free radical. The formation of trichloromethyl radical caused the inactivation of hepatic microsomal calcium pump [41]. 

Hepatocytes make up 60-70% of the total number of liver cells. They have a well-organized intracellular structure with huge numbers of cell organelles to maintain the high metabolic profile. At the apical side or canalicular membrane the cell is specialized for the secretion of bile components. There are several ATP-dependent transport carriers located on this side of the membrane, which transport bile salts, lipids and xenobiotics into the canaliculus. On the sinusoidal side, the cells specialize in uptake and secretion of a wide variety of components. To increase the surface of the membrane for this exchange with the bloodstream, the sinusoidal domain of the membrane is equipped with irregular microvilli. The microvilli are embedded into the fluid and matrix components of the space of Disse and are in close contact with the sinusoidal blood because of the discontinuous and fenestrated SECs. To facilitate its metabolic functions numerous membrane transport mechanisms and receptors are situated in the membrane. 

Lipoprotein metabolism. Entero-cytes release absorbed lipids in the form of triglyceride-rich chylomicrons. Bypassing the liver, these enter the circulation mainly via the lymph and are hydrolyzed by extrahepatic endothelial lipoprotein lipases to liberate fatty acids. The remnant particles move on into liver cells and supply these with cholesterol of dietary origin. 

The answer is A. Recent research has revealed that excess visceral fat deposits secrete several factors that have direct effects on the brain as well as directly on muscle to produce peripheral insulin resistance. Some of these newly identified factors are leptin, re-sistin, and adiponectin, whose mechanisms of action are still under active investigation. Death of pancreatic beta cells is a hallmark feature of type 1 diabetes and may occur only in very advanced stages of type 2 diabetes. Excess adipose in the thighs and buttocks does not contribute as strongly to insulin resistance as does visceral fat, presumably due to a lower level of endocrine activity of such fat depots. Dysfunction of liver lipid metabolism is more a consequence of excess activity of adipose than a cause of insulin resistance. A sedentary lifestyle contributes to build-up of excess fat stores but does not act directly to induce insulin resistance. 

A recent paper clearly highlighted the limitations of in vitro systems in modeling whole-organism responses, which should be considered when developing biomarkers of in vivo toxicity. Dere and colleagues (58) compared the temporal gene expression profiles of Hepalclc mouse hepatoma cells and of the mice liver after treatment with a dioxin. The analysis revealed that Hepalclc cells were able to model the induction of xenobiotic metabolism in vivo. On the other hand, responses associated with cell cycle progression and proliferation were unique to the in vitro system, while lipid metabolism and immune responses were not replicated effectively in the Hepalclc cells. 

This is the accumulation of triglycerides in hepatocytes, and there are a number of mechanisms underlying this response as is discussed below (see the sect. "Mechanisms of Toxicity"). The liver has an important role in lipid metabolism, and triglyceride synthesis occurs particularly in zone 3. Consequently, fatty liver is a common response to toxicity, often the result of interference with protein synthesis, and may be the only response as after exposure to hydrazine, ethionine, and tetracycline, or it may occur in combination with necrosis as with carbon tetrachloride. It is normally a reversible response, which does not usually lead to cell death, although it can be very serious as is the case with tetracycline-induced fatty liver in humans. Repeated exposure to compounds, which cause fatty liver, such as alcohol, may lead to cirrhosis. 

The accumulation of fat is a common cellular response to toxic compounds, which is normally reversible. Usually triglycerides accumulate, although sometimes phospholipids accumulate, as occurs after exposure to the drug chlorphentermine (see chap. 2). Steatosis is particularly common in the liver as this organ has a major role in lipid metabolism (Fig. 6.15). The lipid may appear in the cell as many small droplets or as one large droplet. Interference with lipid metabolism can occur at several points ... 

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. 

Mitochondrial oxidative stress and mitochondrial GSH defense affects transcription factor activation. Oxidant stress in mitochondria not only can promote the loss of mitochondrial GSH and mitochondrial functions, but also can promote extramito-chondrial activation of NF-kB and therefore may affect nuclear gene expression. Mitochondria are targets of cytokines leading to the overproduction of reactive oxygen species induced by ceramide, a lipid intermediate of cytokine action and closely associated with apoptosis. Chronic ethanol intake depletes liver mitochondrial glutathione due to an ethanol-induced defect in the transport of GSH from cytosol into the mitochondrial matirix. This sensitizes liver cells to the prooxidant effects of cytokines and prooxidants generated by the oxidative metabolism of ethanol. 

Lipoproteins are essential for the transport of lipids from the gut and liver to the tissues, and for lipid metabolism. Lipoproteins are spherical particles with a hydrophobic core, covered by a single layer of amphi-pathic molecules phospholipids, cholesterol and one or more apoproteins (of which ten have been isolated these are produced in the liver). The role of these protein coverings is twofold they solubilise hydrophobic lipids and contain cell-targeting signals. 

Liver health. As noted above, a biomarker of choline deficiency is elevated serum ALT levels, which is an indication of liver damage. One of the many functions of the liver is its role in fat metabolism. Without PC, the liver is unable to synthesize lipoproteins. Of particular importance in liver is the synthesis of very low-density lipoproteins (VLDL). With diminished VLDL production, the liver is not able to export lipid. This results in an accumulation of fat in the liver. Lipid accumulation in the liver leads to various stages of liver disease such as liver cell death, fibrosis, cirrhosis, and liver cancer (248-250). The role of choline in liver disease was underscored in the early 1990s when it was determined that patients on extended total parental nutrition (TPN) treatment developed fatty livers (251). At that time, TPN formulas did not include choline. Adding choline (in the form of lecithin) to TPN formulas reversed fatty buildup in these patients, and a... 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

Fat-soluble vitamins require the simultaneous presence of lipids and bile acids for their absorption. In order to be transported to the liver, they are bound to lipoproteins of the chylomicrons. Fat-soluble vitamins are stored in the liver or fatty tissue, often in large amounts and for prolonged periods of time. From there they become available to the intermediary metabolism for complex tasks. Vitamins A and D are secreted from the liver cells by means of carrier proteins. By undergoing biotransformation, fat-soluble vitamins become meta-bolically inactive as well as water-soluble and are thus capable of being excreted, (s. tab. 3.13)... 

So far, no medicament has been found that can achieve a normalization of the disturbed hepatocellular lipid metabolism or bring about the release of the fat stored in liver cells. 

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