Fatty acids liver synthesis

The liver has a variety of functions in lipid metabolism (7.) uptake, oxidation and transformation of free fatty acids, (2.) synthesis of plasma lipoproteins, (3.) trans-... 

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... 

Figure 1. Schematic representation of dicarboxylic fatty acids (DCAs) synthesis and their degradation through L-PBE peroxisomal system, after medium chain triglycerides (MCT) liver absorption (adapted from Hardwick, 2008 Ding et al., 2013).

COMPARTMENTALIZED PYRUVATE CARBOXYLASE DEPENDS ON METABOLITE CONVERSION AND TRANSPORT The second interesting feature of pyruvate carboxylase is that it is found only in the matrix of the mitochondria. By contrast, the next enzyme in the gluconeogenic pathway, PEP carboxykinase, may be localized in the cytosol or in the mitochondria or both. For example, rabbit liver PEP carboxykinase is predominantly mitochondrial, whereas the rat liver enzyme is strictly cytosolic. In human liver, PEP carboxykinase is found both in the cytosol and in the mitochondria. Pyruvate is transported into the mitochondrial matrix, where it can be converted to acetyl-CoA (for use in the TCA cycle) and then to citrate (for fatty acid synthesis see Figure 25.1). /Uternatively, it may be converted directly to 0/ A by pyruvate carboxylase and used in glu-... 

Even though acetate units, such as those obtained from fatty acid oxidation, cannot be used for net synthesis of carbohydrate in animals, labeled carbon from " C-labeled acetate can be found in newly synthesized glucose (for example, in liver glycogen) in animal tracer studies. Explain how this can be. Which carbons of glucose would you expect to be the first to be labeled by "Relabeled acetate ... 

Fatty acid synthesis 1 SREBP-1c, HNF-4a l Expression ACC1, fatty acid synthase Liver... 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

The pentose phosphate pathway is an alternative route for the metabolism of glucose. It does not generate ATP but has two major functions (1) The formation of NADPH for synthesis of fatty acids and steroids and (2) the synthesis of ribose for nucleotide and nucleic acid formation. Glucose, fructose, and galactose are the main hexoses absorbed from the gastrointestinal tract, derived principally from dietary starch, sucrose, and lactose, respectively. Fructose and galactose are converted to glucose, mainly in the liver. 

Fatty acids are synthesized by an extramitochondrial system, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the cytosol. In the rat, the pathway is well represented in adipose tissue and liver, whereas in humans adipose tissue may not be an important site, and liver has only low activity. In birds, lipogenesis is confined to the liver, where it is particularly important in providing lipids for egg formation. In most mammals, glucose is the primary substrate for lipogenesis, but in ruminants it is acetate, the main fuel molecule produced by the diet. Critical diseases of the pathway have not been reported in humans. However, inhibition of lipogenesis occurs in type 1 (insulin-de-pendent) diabetes mellitus, and variations in its activity may affect the nature and extent of obesity. 

Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue but not in liver. Insulin also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and thereby reduces the concentration of... 

Alcoholism leads to fat accumulation in the liver, hyperlipidemia, and ultimately cirrhosis. The exact mechanism of action of ethanol in the long term is stiU uncertain. Ethanol consumption over a long period leads to the accumulation of fatty acids in the liver that are derived from endogenous synthesis rather than from increased mobilization from adipose tissue. There is no impairment of hepatic synthesis of protein after ethanol ingestion. Oxidation of ethanol by alcohol dehydrogenase leads to excess production of NADH. 

Figure 25-6. The synthesis of very low density lipoprotein (VLDL) in the liver and the possible loci of action of factors causing accumulation of triacylglycerol and a fatty liver. (EFA, essential fatty acids FFA, free fatty acids ...

Insulin also plays a role in fat metabolism. In humans, most fatty acid synthesis takes place in the liver. The mechanism of action of insulin involves directing excess nutrient molecules toward metabolic pathways leading to fat synthesis. These fatty acids are then transported to storage sites, predominantly adipose tissue. Finally, insulin stimulates the uptake of amino acids into cells where they are incorporated into proteins. 

In the organism tissues, fatty acids are continually renewed in order to provide not only for the energy requirements, but also for the synthesis of multicomponent lipids (triacylglycerides, phospholipids, etc.). In the organism cells, fatty acids are resynthetized from simpler compounds through the aid of a supramolecular multienzyme complex referred to as fatty acid synthetase. At the Lynen laboratory, this synthetase was first isolated from yeast and then from the liver of birds and mammals. Since in mammals palmitic acid in this process is a major product, this multienzyme complex is also called palmitate synthetase. 

Biosynthesis of Unsaturated Fatty Acids. In the mammalian tissues, the forma-tion of monoene fatty acids is only possible. Oleic acid is derived from stearic acid, and palmitooleic acid, from palmitic acid. This synthesis is carried out in the endoplasmic reticulum of the liver cells via the monooxigenase oxidation chain. Any other unsaturated fatty acids are not produced in the human organism and must be supplied in vegetable food (plants are capable of generating polyene fatty acids). Polyene fatty acids are essential food factors for mammals. 

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