Fatty liver mechanism

The second type of fatty liver is usually due to a metabolic block in the production of plasma lipoproteins, thus allowing triacylglycerol to accumulate. Theoretically, the lesion may be due to (1) a block in apolipoprotein synthesis, (2) a block in the synthesis of the lipoprotein from lipid and apolipoprotein, (3) a failure in provision of phospholipids that are found in lipoproteins, or (4) a failure in the secretory mechanism itself. 

Phytochemicals have little nutritional value and do not get absorbed in the body, but they seem to turn on certain switches in the biochemical mechanisms, which signal the beneficial pathways to maintain health, and to turn off the switches which proceed to adverse biochemical pathways. Rice bran products have demonstrated significant benefits as nutritional therapies in diabetes, hyperlipidemia, cancer, fatty liver, hypercalcuria and heart disease. There is experimental and clinical evidence for the beneficial health effects of the following bioactives of rice bran ... 

In the present compilation of the distribution and pharmacokinetic data of a dozen xenobiotics studied in the dogfish shark, this species yielded excellent data consistent with what we know from similar studies on terrestrial mammals. The data from the shark occasionaly provided information not available in other animals. Major transport parameters in this fish were shown to be similar to those found in mammals. This aquatic organism handles lipid-soluble pollutants by sequestering them in its fatty liver. Together with a previous summary (23) we have now studied about three dozen xenobiotics in this species. Because of its ease of handling, low cost, abundance, predictive value of transport mechanisms, and well-developed pharmacokinetics, the dogfish shark is an ideal fish species to use as a model to study aquatic pollutants. 

Becker E, Messner B, Berndt J. 1987. Two mechanisms of CCK induced fatty liver lipid peroxidation or covalent binding studied in cultured rat hepatocytes. Free Rad Res Commun 3 299- 308. 

Nicotinic acid decreases formation and secretion of VLDL by the liver (mechanism III in Fig. 23.2). This action appears secondary to its ability to inhibit fatty acid mobilization from adipose tissue. Circulating free fatty acids provide the main source of fatty acids for hepatic... 

You M, Crabb DW Recent advances in alcoholic liver disease II. Minireview Molecular mechanisms of alcoholic fatty liver. Am J Physiol Gastrointest Liver Physiol 2004 287 G1. 

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. 

Valproate toxicity is manifested as fatty liver, but what is the underlying mechanism ... 

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) ... 

Phenobarbitone is not only a potentiator of white phosphorus-induced fatty liver, but is also an antagonist of white phosphorus-induced mortality. Pretreatment with phenobarbitone prevented death in phosphorus-treated male rats, while white phosphorus alone caused 40% mortality in males (Jacqueson et al. 1979). The mechanism for this is unclear. 

Pani P, Gravela E, Mazzarino C, et al. 1972. On the mechanism of fatty liver in white phosphorus-poisoned rats. Exp Mol Pathol 16 201-209. 

Hazle JD, Narayana PA, Dunsford HA (1991) In vivo NMR, biochemical, and histologic evaluation of alcohol-induced fatty liver in rat and a comparison with CC14 hepatotoxic-ity. Magnetic Resonance in Medicine 19 124-135 Hockings PD, Busza AL, Byrne J et al. (2003a) Validation of MRI measurement of cardiac output in the dog The effects of dobutamine and minoxidil. Toxicology Mechanisms Methods 13 39-43... 

The development of liver steatosis is attributable to various exogenous and endogenous mechanisms, which may combine with and/or potentiate each other, (s. tab. 31.1) Numerous causal factors must be considered in the pathogenesis of fatty liver, (s. tabs. 31.5, 31.7)... 

Tht fatty liver condition can be described as follows. With alcohol consumption, the liver s main source of energy (fatly acids) is replaced by alcohol. This results in accumulation of unused fatty acids, in the form of triglycerides, with the consequent deposition of these TGs as fat. This mechanism is different from the fatty liver provoked by kwashiorkor, where a fatty liver results from the failure to synthesize the apoHpopioteins needed for exporting TGs from the liver. The fatty liver of kwashiorkor is not associated with cirrhosis, but that of alcoholism is associated with conversion of stellate cells to cells resembling those of connective tissue, i-c-, fibroblasts, Stellate cells are fat-storing cells that occur In the interstitial space between the capillaries and hcpalocytcs, called the space of Disse. 

Lieber CS.. Alcoholic fatty liver Its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol2004 34(1) 9 19. 

Alcohol is metabolized to acetaldehyde by cytosolic ADH and the MEOS (primarily GYP 2E1— the same cytochrome p45o dependent enzyme involved with acetaminophen metabolism). Acetaldehyde is subsequently metabofized to acetyl-CoA by AADH. This is further broken dovra to acetate, which is either converted to carbon dioxide and water or enters the citric acid cycle to be converted to fatty acids. The latter is a major mechanism for induction of fatty liver by alcohol, but acetaldehyde is probably the primary toxin. It causes most of the injury to liver cells as well as the induction of collagen synthesis leading to fibrosis and, ultimately, cirrhosis. 

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. 

Fatty liver is a description for the abnormal accumulation of fat (mainly triglycerides) in the hepatic parenchymal cells this occurs with several xenobiotics, but fat accumulation does not always equate to liver damage. In the liver, smaller Ito (or fat-storing or stellate) cells differentiate into myofibroblastic cells and form collagen. Several mechanisms can be implicated in the development of fatty liver (Henderson 1963 Lombardi 1966 Shift, Roheim, and Eder 1971). These mechanisms include ... 

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