Lipid accumulation

An atherosclerotic lesion consisting of a fibrotic cap surrounding a lipid-rich core. The lesion is the site of inflammation, lipid accumulation, and cell death. Also know as an atheroma. 

Vincristine a severe polyneuropathy is a particularly common side effect, but in some patients a painful autophagic myopathy is also present. Abnormal lysosomal complexes are also formed which function as virtually indigestible lipid accumulations. 

Disease Enzyme Deficiency Lipid Accumulating Clinical Symptoms... 

This chapter surveys the neurochemistry of lipid messengers, as well as the mechanisms by which bioactive lipids accumulate upon stimulation in response to injury, cerebral ischemia, seizures, neurotrauma or neurodegen-erative diseases, and their significance in pathophysiology. Emphasis is placed on three groups of bioactive lipids AA and its metabolites, known collectively as eicosanoids PAF, a highly potent ether phospholipid and the newly identified DHA-derived mediator, neuroprotectin Dl. 

Uno, S., et. al., Cyplal(-/-) male mice Protection against high dose TCDD-induced lethality and wasting syndrome, and resistance to intrahepatocyte lipid accumulation and urophorhyria, Toxicol. Appl. Pharmacol., 196, 410, 2004. 

Unlike the previously discussed compounds, which inhibit MTP in both liver and intestine, an intestine-selective orally-active MTP inhibitor JTT-130 (structure not yet disclosed) has been reported to decrease plasma cholesterol and TG in guinea pigs with no hepatic lipid accumulation [16]. Although further studies in human are needed, inhibitors that selectively target intestinal MTP might be a safer alternative as a treatment for hyperlipidemia than the liver-targeting MTP inhibitors. 

Bll. Bersot, T. P., Innerarity, T. L., Pitas, R. E., Rail, S. C., Weisgraber, K. H., and Mahley, R. W., Fat feeding in humans induces lipoprotein of density less than 1.006 that are enriched in apolipoprotein(a) and that cause lipid accumulation in macrophages. J. Clin. Invest. 77, 622-630 (1986). 

Oxidized LDL alter cellular functions role in cell death Oxidized LDL seem to be poorly degraded by lysosomal enzymes and accumulate in lysosomes altering in turn their functionality (Dean et al., 1997). It has been proposed that inhibition of oxidized LDL degradation and subsequent lipid accumulation may induce a destabilization of the acidic compartment, and lysosomal rupture with a relocation of lysosomal enzymes in the cytosol (li W et al, 1998). This process, also called endopepsis , occurs early and could precede mitochondrial dysfunction and cell death (Lossel et al., 1994). Moreover, oxidized LDL trigger a dysfunction of the intracellular proteolytic ubiquitin/proteasome pathway (early activation followed by inhibition)... 

Accumulation of cytoplasmic NADH and glycerol 3-P may also contribute to lipid accumulation in alcoholic liver disease. Free fatty acids released from adipose in part enter the liver where P-oxidation is very slow (high NADH). In the presence of high glycerol-3P, fatty acids are inappropriately stored in the liver as triglyceride. 

As the fatty streak enlarges over time, necrotic tissue and fiee lipid accumulates, surrounded by epithelioid cells and eventually smooth muscle cells, an advanced plaque with a fibrous cap. The plaque eventually begins to occlude the blood vessel, causing ischemia and infarction in the heart, brain, or extremities. 

Other Systemic Effects. Adrenal fibrosis with lipid accumulation was reported in one study in mice, but these effects have not been observed in humans known to be exposed to heptachlor and have not been verified in other species. There has been no measurement of adrenal hormone in exposed humans or animals. Body weight changes have, in general, been accompanied by a decrease in food consumption, due possibly to taste aversion. 

The hepatocytes, or parenchymal cells, represent about 80% of the liver by volume and are the major source of metabolic activity. However, this metabolic activity varies depending on the location of the hepatocyte. Thus, zone 1 hepatocytes are more aerobic and therefore are particularly equipped for pathways such as the p-oxidation of fats, and they also have more GSH and GSH peroxidase. These hepatocytes also contain alcohol dehydrogenase and are able to metabolize allyl alcohol to the toxic metabolite acrolein, which causes necrosis in zone 1. Conversely, zone 3 hepatocytes have a higher level of cytochromes P-450 and NADPH cytochrome P-450 reductase, and lipid synthesis is higher in this area. This may explain why zone 3 is most often damaged, and lipid accumulation is a common response (see "Carbon Tetrachloride," for instance, chap. 7). 

Due to their lipophilic nature, PCBs tend to accumulate or reside in those environmental compartments that are non-polar and are amenable to lipid accumulation, such as the organic components of sediments. PCB presence in polar substances, such as water, is minimal. PCBs are not volatile and thus do not persist in air in any appreciable concentration. Therefore, the major sources of environment exposure to environmental species remain soils and sediments. 

Fatty liver refers to the abnormal accumulation of fat in hepatocytes. At the same time there is a decrease in plasma lipids and lipoproteins. Although many toxicants may cause lipid accumulation in the liver (Table 14.1), the mechanisms may be different. Basically lipid accumulation is related to disturbances in either the synthesis or the secretion of lipoproteins. Excess lipid can result from an oversupply of free fatty acids from adipose tissues or, more commonly, from impaired release of triglycerides from the liver into the plasma. Triglycerides are secreted from the liver as lipoproteins (very low density lipoprotein, VLDL). As might be expected, there are a number of points at which this process can be disrupted. Some of the more important ones are as follows (Figure 14.1) ... 

The role that fatty liver plays in liver injury is not clearly understood, and fatty liver in itself does not necessarily mean liver dysfunction. The onset of lipid accumulation in the liver is accompanied by changes in blood biochemistry, and for this reason blood chemistry analysis can be a useful diagnostic tool. 

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