Fuel Sensors 421 Fatty Acids

As described in Section 2., fatty acids in blood are an important alternative fuel to glucose but, in addition, they have a role as a messenger or "hormone" indicating changes in dietary conditions. For example, fatty acid levels in blood will rise during starvation, as fat reserves in the body are released into blood. Similarly, fatty acid levels may rise under KD-induced conditions of calorie restriction (semistarvation) and high-fat intake. The major sensor of fatty acids in hepatocytes is the peroxisome proliferator-activated receptor alpha (PPARa) protein. PPARa is a fatty acid-activated transcription factor that is critical to the genetic reprogramming of hepatocyte metabolism in response to starvation (9). It possesses a broad binding specificity for such fatty acid activators, ranging from long-chain to medium-chain fatty acids (10). Similar to gluco-corticoid receptors, PPARa is located in the nucleus of hepatocytes. Thus, fatty acids entering the hepatocyte bind and activate PPARa, resulting in alterations in the expres-

Fig. 2. Fed-to-starved switch alters expression of a battery of PPARa-regulated genes encoding key enzymes of intermediary metabolism. (A) Fed state. (B) Starved state. Selected (see ref. 11) PPARa-regulated genes are italicized and underscored, with font size used to indicate up- or downregulation of gene expression between the fed and starved states. Abbreviations: ACS1, acyl-CoA synthetase 1; CPT1a, carnitine palmitoyl transferase 1a; PDK4, pyruvate dehydrogenase kinase 4; HMGCS2, mito-chondrial 3-hydroxy-3-methylglutaryl-CoA synthetase; GOT1, cytosolic glutamate-oxaloacetate transaminase; ASS1, arginosuccinate synthetase.

Fig. 2. Fed-to-starved switch alters expression of a battery of PPARa-regulated genes encoding key enzymes of intermediary metabolism. (A) Fed state. (B) Starved state. Selected (see ref. 11) PPARa-regulated genes are italicized and underscored, with font size used to indicate up- or downregulation of gene expression between the fed and starved states. Abbreviations: ACS1, acyl-CoA synthetase 1; CPT1a, carnitine palmitoyl transferase 1a; PDK4, pyruvate dehydrogenase kinase 4; HMGCS2, mito-chondrial 3-hydroxy-3-methylglutaryl-CoA synthetase; GOT1, cytosolic glutamate-oxaloacetate transaminase; ASS1, arginosuccinate synthetase.

sion of many genes encoding enzymes of intermediary metabolism (Fig. 2). This results in changes in cellular concentrations of such enzymes and, therefore, changes in the flow of fatty acids, glucose, and amino acids through the hepatocyte. For example, when PPARa is activated in the mouse liver by starvation, it causes an increase in fatty acid oxidation, an increase in ketogenesis, a decrease in glucose oxidation, and a decrease in amino acid transamination and deamination (11) (Fig. 2). In addition, blood levels of insulin and glucocorticoids alter the expression of the PPARa gene, hence the concentration of PPARa protein available for fatty acid activation (12). It can be seen, therefore, that activation of PPARa by a variety of blood-borne dietary signals results in an integrated metabolic response through reprogramming expression of genes encoding enzymes of hepatocyte intermediary metabolism. Three such genes regulated by PPARa, in human hepatocyte-derived cell lines, encode the key branch-point enzymes of FAOK described earlier, namely ACS1, CPTla, and HMGCS2 (13). In the next section, I examine the regulation of HMGCS2 in more detail, with reference to its regulation by the KD.

4.2.2. Amino Acids and Sugars

Considerably less is known about the existence of molecular sensors in hepatocytes for changes in blood amino acid or sugar fuels. However, there is recent evidence to suggest that certain amino acids, and sugars such as glucose, may have specific cellular receptors that can affect genetic reprogramming, as already described for PPARa and fatty acids. For example, the proto-oncogene transcription factor c-myc may be impor tant in mediating appropriate increases in glycolysis and decreases in gluconeogenesis and ketogenesis in response to increases in blood glucose fuel. Thus, glucose acts indirectly to decrease hepatocyte HMGCS2 expression via increases in c-myc expression that in turn decrease PPARa expression and hence PPARa activity (14). However, the details of such pathways, and the sensors that directly interact with glucose and various amino acids remain to be established.

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