Synthesis lipid

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid synthesis, protein synthesis). 

Increased lipid synthesis/inhibi-tion of lipolysis Activation of lipoprotein lipase (LPL)/induc-tion of fatty acid synthase (FAS)/inactivation of hormone sensitive lipase (HSL) Facilitated uptake of fatty acids by LPL-dependent hydrolysis of triacylglycerol from circulating lipoproteins. Increased lipid synthesis through Akt-mediated FAS-expression. Inhibition of lipolysis by preventing cAMP-dependent activation of HSL (insulin-dependent activation of phosphodiesterases )... 

The main metabohtes produced by Monascus are polyketides formed by the condensation of one acetylcoA with one or more malonylcoAs with a simultaneous decarboxylation as in the case of lipidic synthesis. They consist of the pigments, monacohns, and under certain conditions a mycotoxin. 

With the exception of the acetyl-CoA thiolase, all these enzymes are located exclusively in the peroxisomes, whereas the enzymes that are involved in lipid synthesis are found in the microsomes and the mitochondrion. 

The lipotropic factors exercise a marked effect on the biosynthesis of phospho-lipids and triglycerides. As has been mentioned above, they facilitate the phospho-lipid synthesis. The dietary deficiency of lipotropic factors favours the triglyceride production in the organism. 

DeNiro, M. J. and Epstein, S. (1977) Mechanism of carbon isotope fractionation associated with lipid synthesis. Science 197, 261 263. 

Mutant or knockout mice defective in specific enzymes involved in lipid synthesis have provided powerful tools for genetic analysis of lipid function in the nervous system. For example, disruption of the genes for ceramide galactosyl transferase or galactosyl ceramide sulfotransferase,... 

Patel, M. S., Johnson, C. A., Rajan, R. etal. The metabolism of ketone bodies in developing human brain development of ketone-body-utilizing enzymes and ketone bodies as precursors for lipid synthesis. /. Neurochem. 25 905-908, 1975. 

Because of the polyfactorial nature of disease states, such as obesity, type 2 diabetes, and Metabolic Syndrome, it is expected that drugs targeting the lipid synthesis and metabolism pathways will be used in the context of combination therapy [7]. Pre-clinical and clinical results to date indicate that pronounced efficacy could be achieved toward the management of associated lipid levels and insulin resistance, and thus, investigation in these areas provides significant promise. 

In mammalian cells, the final stage of PS biosynthesis occurs in ER and MAM (Trotter and Voelker, 1994 Daum and Vance, 1997 Voelker, 2000). The other membranes in the ceU, such as mitochondria, nucleus, and plasma membrane, are therefore assembled from PS exported from ER and MAM (Figure 2). Phospholipid synthesis in mitochondria is restricted to the formation ofphosphatidylglycerol, cardiolipin, and PE, and other lipids such as PC and PS must be imported from sites of cellular lipid synthesis, ER or MAM (Daum, 1985 Vance, 1991). PS imported to the outer mitochondrial membrane is then translocated to the inner mitochondrial membrane, where it is converted to PE by PS decarboxylase (PSD) (Dennis and Kennedy, 1972 Voelker, 1990). It has been shown that the translocation of PS to mitochondria followed by its decarboxylation is a major pathway for the synthesis of PE in some cultured mammahan cells (Voelker, 1984 Kuge et al, 1986 Voelker and Frazier, 1986), suggesting that significant amounts of PE found in cell membranes are derived from mitochondria. 

Rusinol, A.E., Cui, Z, Chen, M.H., and Vance, J.E., 1994, A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins. J. Biol. Chem., 269 27494-27502. 

Plants hold the record for the amount of lipid synthesis that occurs in the world. They are of considerable economic importance, particularly in the production of human and animal food, and currently as a fuel for cars and for generating electricity. 

Sugar The hydrolysis of sucrose in the intestine produces both glucose and fructose, which are transported across the epithelial cells by specific carrier proteins. The fructose is taken up solely by the liver. Fructose is metabolised in the liver to the triose phosphates, dihydroxy-acetone and glycer-aldehyde phosphates. These can be converted either to glucose or to acetyl-CoA for lipid synthesis. In addition, they can be converted to glycerol 3-phosphate which is required for, and stimulates, esterification of fatty acids. The resulting triacylglycerol is incorporated into the VLDL which is then secreted. In this way, fructose increases the blood level of VLDL (Chapter 11). 

Bile helps in the digestion and absorption of fats. Its constituent bile acids (BAs) have detergent properties, and some can be carcinogenic. BAs can act as signalling molecules, entering the nuclei and reacting with the nuclear receptors and this could enhance or reduce BA synthesis. In this way, they control their own levels as well as those of their precursor, cholesterol. This controls cholesterol homeostasis and BA and lipid synthesis. 

Membrane-located enzymes in the sER catalyze lipid synthesis. Phospholipid synthesis (see p. 170) is located in the sER, for example, and several steps in cholesterol biosynthesis (see p. 172) also take place there. In endocrine cells that form steroid hormones, a large proportion of the reaction steps involved also take place in the sER (see p. 376). 

The 3 10 cells in the liver—particularly the hepatocytes, which make up 90% of the cell mass—are the central location for the body s intermediary metabolism. They are in close contact with the blood, which enters the liver from the portal vein and the hepatic arteries, flows through capillary vessels known as sinusoids, and is collected again in the central veins of the hepatic lobes. Hepatocytes are particularly rich in endoplasmic reticulum, as they carry out intensive protein and lipid synthesis. The cytoplasm contains granules of insoluble glycogen. Between the hepatocytes, there are bile capillaries through which bile components are excreted. 

Protein synthesis Lipid synthesis Proliferation Glucose transport Statl/Stat3 activation She phosphorylation c-fos induction SOCSl binding... 

The dicarboximides inhibit spore germination and cause increased branching, swelling and lysis of germ tubes and hyphal tips. Effects on cell division have been reported but no major inhibition of nucleic acid metabolism, respiration, protein or lipid synthesis has been observed. 

Glycerol for milk lipid synthesis is obtained in part from hydrolysed blood lipids (free glycerol and monoglycerides), partly from glucose and a little from free blood glycerol. Synthesis of triglycerides within the cell is catalysed by enzymes located on the endoplasmic reticulum, as shown in Figure 3.13. 

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). 

Depletion of ATP is caused by many toxic compounds, and this will result in a variety of biochemical changes. Although there are many ways for toxic compounds to cause a depletion of ATP in the cell, interference with mitochondrial oxidative phosphorylation is perhaps the most common. Thus, compounds, such as 2,4-dinitrophenol, which uncouple the production of ATP from the electron transport chain, will cause such an effect, but will also cause inhibition of electron transport or depletion of NADH. Excessive use of ATP or sequestration are other mechanisms, the latter being more fully described in relation to ethionine toxicity in chapter 7. Also, DNA damage, which causes the activation of poly(ADP-ribose) polymerase (PARP), may lead to ATP depletion (see below). A lack of ATP in the cell means that active transport into, out of, and within the cell is compromised or halted, with the result that the concentration of ions such as Na+, K+, and Ca2+ in particular compartments will change. Also, various synthetic biochemical processes such as protein synthesis, gluconeogenesis, and lipid synthesis will tend to be decreased. At the tissue level, this may mean that hepatocytes do not produce bile efficiently and proximal tubules do not actively reabsorb essential amino acids and glucose. 

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