De novo lipogenesis

In situations where carbohydrates, proteins and fats are ingested in high amounts, excess dietary fat can easily be stored as TAG in adipose tissue. The storage capacity for carbohydrates in the form of glycogen is limited, however, and in humans no protein has been identified whose sole function is to serve as an amino acid reservoir. Therefore, the body must be capable of transforming surplus non-fat energy into fat. This process is called de novo lipogenesis (DNL). In humans, DNL occurs in the liver and, possibly to a lesser extent, in adipose tissue (Hellerstein et al. 1996). Obviously, the key component of DNL is the biosynthesis of FFA - mainly palmitate -which is a complex process that starts from acetyl-coenzyme A (CoA) and takes place in the cytosol (Fig. 1.1). Acetyl-CoA is generated in the mitochondria, but citrate and not acetyl-CoA is transported into the cytosol. There, the citrate is cleaved to acetyl-CoA and oxaloacetate by the enzyme ATP-citrate lyase (CL). The enzyme acetyl-CoA carboxylase (ACC) catalyzes the production of malonyl-CoA. This is the controlling step in fatty acid synthesis. The fatty acid synthase (FAS) is responsible for the overall synthesis of fatty acids. It is a single polypeptide containing seven distinct enzymatic activities. FAS catalyzes a series of condensation reactions each accompanied by decarboxylation and two reductions with the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) as a hydrogen donor, and this reaction is repeated until formation of a palmitate molecule is achieved (Hellerstein et al. 1996). DNL is stimulated by a low-fat, high-carbohydrate diet in weight-stable human subjects (Hudgins et al. 1996), but it is generally assumed that fatty acid biosynthesis is an unimportant metabolic pathway in humans. Schwarz et al. (1995) quantified that even humans receiving a diet with 50% energy surplus as carbohydrate synthesize less than 5 g fatty acids in the liver per day. Yet, we have to keep in mind that: (a) it is difficult to assess DNL in humans (Schutz 2004) and that (b) it is unknown how longer-term overfeeding with a high-carbohydrate diet affects DNL in lean and obese subjects (Schutz 2000). Furthermore,

Novo Lipogenesis Humans

Fig. 1.1 Diagram depicting the effects of several substances on DNL and CPT 1 activity: dashed arrow, activation; dotted arrow, inhibition. Abbreviations: ACC, acetyl-CoA carboxylase; AS, amino acids; CL, ATP-citrate lyase; CPT 1, carnitine palmitoyl transferase 1; FAS, fatty acid synthase; Fru, fructose; Glu, glucose; HCA, hydroxycitric acid; MCD, malonyl-CoA decarboxylase; OAA, oxaloacetate; PPAR-a, peroxisome proliferator-activated receptor-a; TCA, tricarboxylic acid; LCFA-CoA, long-chain fatty acid-CoA; P, phosphate; n-3 PUF A, n-3 polyunsaturated fatty acid.

Fig. 1.1 Diagram depicting the effects of several substances on DNL and CPT 1 activity: dashed arrow, activation; dotted arrow, inhibition. Abbreviations: ACC, acetyl-CoA carboxylase; AS, amino acids; CL, ATP-citrate lyase; CPT 1, carnitine palmitoyl transferase 1; FAS, fatty acid synthase; Fru, fructose; Glu, glucose; HCA, hydroxycitric acid; MCD, malonyl-CoA decarboxylase; OAA, oxaloacetate; PPAR-a, peroxisome proliferator-activated receptor-a; TCA, tricarboxylic acid; LCFA-CoA, long-chain fatty acid-CoA; P, phosphate; n-3 PUF A, n-3 polyunsaturated fatty acid.

DNL also contributes to multiple cellular processes. McGarry and Foster (1980) found that malonyl-CoA, the first intermediate product of DNL, is a potent inhibitor of the carnitine palmitoyl transferase 1 (CPT 1), the enzyme that catalyses the rate-controlling step in mitochondrial fatty acid oxidation (Foster 2004) (Fig. 1.1). This finding might explain why so many non-lipogenic tissues, such as heart and brain, also express enzymes of DNL; the ability to generate malonyl-CoA allows cells to block mitochondrial fatty acid oxidation quickly by switching to carbohydrate utilization. The finding that certain neurons in the brain, notably in the hypothalamus, express enzymes involved in DNL and fatty acid oxidation is surprising because under normal conditions the brain almost exclusively metabolizes glucose (Seeley and York 2005). Presumably, intermediates in the DNL pathway, such as malonyl-CoA, serve as energy sensors that signal higher brain centers to produce appropriate responses, i.e. changes in food intake and energy expenditure (Dowell et al. 2005). Therefore, DNL in specialized neurons of the brain appears to play a crucial role in the control of energy balance (Ronnett et al. 2005).

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