Intrahepatic Regulation

There are situations (e.g., stress) where the supply of fatty acids to the liver may be increased, but there is no necessity to increase the availability of ketone bodies to the peripheral tissues. Consequently, there is a requirement that the rate of hepatic keto-genesis should be controlled independently of the supply of fatty acids. However, it must be stressed that without an increase in the supply of fatty acids the rate of ketogenesis cannot increase.

Adipose tissue

Adipose tissue

Figure 3 Role of ketone bodies as feedback regulators.

Much of the current interest is concerned with how the intrahepatic metabolism of fatty acids (Figure 4) is regulated. Long-chain fatty acids entering the liver have three main fates:

1. They can be re-esterified to phospholipids and triacylglycerols and then be secreted as very low-density lipoproteins (VLDL).

2. They can be oxidized via the mitochondrial ,3-oxi-dation complex to acetyl-CoA. The latter can combine with another molecule of acetyl-CoA in the reaction catalysed by acetoacetyl-CoA thio-lase and then enter the hydroxymethylglutaryl-CoA pathway to form acetoacetate.

3. The acetyl-CoA derived from the fatty acids can be completely oxidized in the tricarboxylate cycle.

The short- and medium-chain fatty acids cannot be re-esterified to any appreciable extent in mammalian liver and therefore they are either metabolized to ketone bodies or completely oxidized. In addition, unlike the long-chain fatty acids, they are transported directly into the mitochondrial matrix without the need to be converted first to the corresponding acyl-CoA derivatives.

The role of malonyl CoA The entry of free long-chain fatty acids into the hepatocyte is via a specific carrier on the plasma membrane. Once inside the cytosol the long-chain fatty acids are bound to binding proteins, converted to the acyl-CoA derivatives, and then can either be esterified or enter

BLOOD

Nonesterified fatty acid (albumin-bound)

CYTOSOL

Nonesterified fatty acids (binding protein)

Fatty acyl-CoA

Glycerol-3-phosphate

Triacylglycerols Phospholipids

Short- and medium chain fatty acids

MATRIX

Fatty acyl-CoA

Carnitine

Fatty acyl-CoA

Carnitine

Fatty acyl-CoA

Oxaloacetate f Citrate + CoA Acetoacetyl-CoA + CoA

Hydroxymethylglutaryl-CoA (k)j

Acetoacetate + acetyl-CoA -(l)

3-Hydroxybutyrate

Figure 4 Pathway of fatty acid catabolism in liver. Enzymes involved: (a) long-chain fatty acyl-CoA synthetase; (b) glycerol-3-phosphate acyl-CoA transferase; (c) CAT I; (d) CAT II; (e) carnitine exchange; (f) short- and medium-chain fatty acyl-CoA synthetase; (g) fatty acid oxidation complex; (h) citrate synthase; (i) acetoacetyl-CoA thiolase; (j) hydroxymethylglutaryl-CoA synthase; (k) hydroxymethylglutaryl-CoA lyase; (l) hydroxybutyrate dehydrogenase; (m) tricarboxylate cycle.

the mitochondria via a complex transport system, the carnitine-acyl-CoA transferase (CAT) system. This consists of two proteins: CAT I located on the outer mitochondrial membrane and CAT II on the inner mitochondrial membrane (Figure 5). The overall action of the two enzymes results in the transfer of a long-chain fatty acyl-CoA to the mitochondrial matrix and the return of free carni-tine to the cytosol via an exchange mechanism. Although carnitine is not consumed in the reaction, the available concentration can be critical. In nutritional carnitine deficiency there is impairment of long-chain fatty acid oxidation and ketogenesis.

The activity of CAT I is the key to the intrahepa-tic regulation of fatty acid metabolism in most situations. Its activity increases in ketogenic situations. More importantly, CAT I is inhibited by malonyl-CoA and the sensitivity of CAT I to this inhibitor changes in various pathophysiological situations such as fasting or diabetes.

As malonyl-CoA is a key intermediate in the synthesis of fatty acids (lipogenesis) from products (pyruvate and lactate) of glucose metabolism, this interaction provides a regulatory link between lipid and carbohydrate metabolism (Figure 5). Thus on high-carbohydrate diets, when the rate of hepatic lipogenesis, and consequently the cytosolic concentration of malonyl-CoA, is high, the activity of CAT I will be inhibited and fatty acids will be diverted to esterified products and secretion as VLDL rather than oxidation and conversion to ketone bodies. Conversely, on high-fat diets or in starvation, when lipogenesis is inhibited, malonyl-CoA concentration is low and CAT I is active. The sensitivity of CAT I to malonyl-CoA generally correlates with the prevailing concentration of the latter.

The short- and medium-chain fatty acids do not utilize the CAT I and II system to enter the mito-chondrial matrix and therefore their oxidation is not greatly influenced by the prevailing 'carbohydrate status' (amount of glycogen, direction of carbohydrate flux, glycolysis, or gluconeogenesis) of the liver (Figure 5).

Insulin can rapidly depress the rate of ketogenesis in vitro. This effect is thought to result mainly from its stimulatory action on a key enzyme of lipogen-esis, acetyl-CoA carboxylase, which in turn increases the concentration of malonyl-CoA. Glucagon and the catecholamines have the opposite effect. Thus hormonal effects can be exerted at both the extra-hepatic (lipolysis) and intrahepatic (modulation of lipogenesis) levels.

Intramitochondrial regulation Once the fatty acyl-CoA molecule is attached to the mitochondrial /3-oxidation complex there appears to be little regulation exerted until release of the acetyl-CoA fragments. As indicated above, the acetyl-CoA can enter the tricarboxylate cycle and be oxidized to CO2 or can be converted to ketone bodies via the hydroxy-methylglutaryl-CoA pathway.

It appears that in most experimental situations the complete oxidation of fatty acids proceeds at a low, but relatively similar, rate and it is the activity of the

Glycogen

Glucose

Long-chain fatty acids

Very low-density lipoproteins Medium-chain fatty acids Acetoacetate

3-Hydroxybutyrate

BLOOD

Glucose 6-phosphate

Oxaloacetate Acetyl-CoA -t

Pyruvate

Citrate

Oxaloacetate Acetyl-CoA -t

Citrate

Fatty acyl-CoA

r *

Triacylglycerols (esterified products)

Carnitine

Triacylglycerols (esterified products)

Carnitine

Acetyl-CoA

Oxaloacetate

Citrate

CYTOSOL

Fatty acyl-CoA

Carnitine

Fatty acyl-CoA -

Acetyl-CoA Acetoacetate

3-HydroXybutyrate

MITOCHONDRIA

Figure 5 Interrelationship between hepatic carbohydrate metabolism, lipogenesis, and ketogenesis. Circled minus signs indicate inhibition by the metabolite.

hydroxymethylglutaryl-CoA pathway that shows larger changes. This has led to the view that the pathway might be regulated by mechanisms other than substrate supply.

Studies on the expression of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) synthase have shown that both the mRNA coding for the protein and the amount of protein increase during the onset of ketogenic states (fasting, diabetes) and that these changes are rapidly reversed (refeeding, insulin treatment). However, the finding that rates of keto-genesis from medium-chain fatty acids (CAT I and II) do not alter greatly with change in physiological state, if the rate of fatty acid supply is held constant, would seem to rule out appreciable regulation within the hydroxymethylglutaryl-CoA pathway. Indeed, current thinking suggests that the activity of CAT I is the primary intrahepatic site for the regulation of fatty acid oxidation and ketogenesis. If there is another important site, particularly during situations associated with the reversal of ketogenesis, it is likely to be proximal to the step catalysed by this protein (e.g., the supply of fatty acids to the liver). Thus in vivo there is little doubt that the primary step that controls ketogenic flux is the rate of long-chain fatty acid release from adipose tissue.

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