Fatty Acid Oxidation

Basic Mechanisms Mitochondrial b-oxidation of fatty acids is a principal source of generation of ATP, the conserved form of energy, in liver, heart, and kidney. Because of their amphiphilic nature, fatty acids become easily associated with mitochondrial membranes. In order to enter the mitochondrial ß-oxidationprocess, they have to pass the outer and inner mitochondrial membrane before further processing in the mitochondrial matrix. Short and medium-chain fatty acids can cross the mitochon-drial membranes without prior activation. Long-chain fatty acids (C14-C18) first require conversion into acyl-carnitine fortranslocation across the inner mitochondrial membrane ("carnitine shuttle"), before further processing after carnitine removal occurs. The resulting acyl-CoA then undergoes ß-oxidation, resulting in the generation of reducing NADH equivalents that are subsequently oxidized by the mitochondrial respiratory chain. The energy thus produced is stored in the form of ATP by the oxidative phosphorylation system, coupled with the transfer of electrons along the respiratory chain [198]. A severe and long-lasting impairment ofhepatic ß-oxidation is a fundamental mechanism of metabolic organ failure. Morphologically, this results in microvesicular steatosis as the result of accumulation of nonmetabolized fatty acids and their re-esterification into triglycerides.

Actions of Salicylates Inhibition of hepatic mitochondrial ß-oxidation of fatty acids, predominantly long-chain, is obtained at millimolar concentrations of aspirin or salicylate in vitro [199] and a typical feature of high-dose aspirin treatment or overdosing, These impairments may result from deficiency in cofactors such as coenzyme A (CoA) or carnitine that are essential for fatty acid transport and metabolism and become exhausted as a result of formation of acyl derivatives, such as salicylyl-CoA [200] (Figure 2.21). This will impair the activation of long-chain fatty acids by preventing their passage through the mitochondrial membranes, eventually resulting in intracellular but extramito-chondrial accumulation and a number of secondary effects, including re-esterification into triglycerides and formation of dicarboxylic acids. Marked changes in liver fatty acid metabolism were found in liver biopsy specimens of patients with rheumatoid arthritis after long-term treatment with highdose aspirin [201].

The hepatic lipid distribution pattern was studied in liver specimens obtained at autopsy from seven patients with rheumatoid arthritis. All patients had taken 3-6 g aspirin daily for many years. They were compared with seven age-matched controls who had not taken aspirin. All patients of both groups died from myocardial infarction, and there was no known functional liver abnormality at the time of death.

The total lipid content was significantly, >20%, higher in liver biopsy specimens of aspirin-treated patients as opposed to age-matched controls without aspirin intake. Most striking differences were seen in free fatty acids, which were more than doubled in aspirin-treated patients, whereas total hepatic phospholipids were reduced by >30%. The phospholipid depletion was due to a considerable, about 40-50%, decrease in phospha-tidylethanolamine, phosphatidylcholine, and cardiolipin though other phospholipid classes remained unchanged.

It was concluded that major metabolic impairments of fatty acid oxidation occur in patients at long-term (years) high-dose aspirin treatment (Table 2.10). The increase in neutral lipids and free fatty acids in these patients suggest reduced oxidative capacity, indicating a relationship between abnormalities in fatty acid oxidation and aspirin intake [201].

Unfortunately, this study did not analyze the composition of the free fatty acid fraction, specifically the percentage of long-chain fatty acids or the occurrence of dicarboxylic acids. Nor was there any morphological data of the liver specimens. Thus, there was no information about microvesicular steatosis. It is also interesting that despite the markedly elevated free fatty acids, there was no

Figure 2.21 Mitochondrial ß-oxidation of short (SC), medium (MC), and long-chain fatty acids and their modification by salicylate (for further explanation, see the text).

increased esterification in triglycerides. These data differ from animal studies with high-dose short-term aspirin treatment where increased triglycerides are a regular finding [199]. Of interest are also the marked reductions in phospholipids, possibly indicating an altered lipid signaling related to changes in membrane conductance. Unfortunately, apparently no further studies on this issue were conducted in men and probably will not be done in the future because high-dose long-term aspirin treatment is no longer the treatment of choice for these patients. Thus, it will probably never become elucidated whether aspirin-induced long-term changes in hepatic lipid metabolism are a general finding or superimposed to the altered immuno-logic status of rheumatic patients (Section 3.2.3).

Disturbed "Carnitine Shuttle" Like other fatty acids, salicylate is activated to salicylyl-CoA in mitochondria by a medium-chain fatty acid - CoA ligase [202]. This activation is a prerequisite for conjugation with glycine to form salicyluric acid [81] (Section 2.1.2). Generation of large amounts of salicylyl-CoA in the presence of high salicylate levels will deplete the cellular stores of coenzyme A and possibly carnitine (Figure 2.21). As a consequence, less carnitine and CoA are available for transport of long-chain fatty acids to the mitochondrial matrix and subsequent ß-oxidation. In experimental studies, the reduced ß-oxidation of long-chain fatty acids could be prevented by addition of carnitine and CoA to avoid exhaustion of these compounds [199]. Secondary events of disturbed ß-oxidation are inhibition of gluconeogenesis and ureagenesis, though there is in vitro evidence that disturbed ureagenesis by salicylates can also be shown independent of its action on uncoupling of oxidative phosphorylation [203].

Appearance of Dicarboxylic Fatty Acids Another feature of impaired mitochondrial ß-oxidation of long-chain fatty acids and their local accumulation is the appearance of long-chain dicarboxylic fatty acids as products of their omega-oxidation [204]. These acids are natural uncouplers of oxidative phosphorylation. Their physicochemical proper-

Table 2.10 Liver lipid composition in seven patients treated for years with 3.25-5.85 g aspirin daily as compared to seven age-matched controls.

CON Aspirin

Neutral lipids

CON Aspirin

Neutral lipids

Table 2.10 Liver lipid composition in seven patients treated for years with 3.25-5.85 g aspirin daily as compared to seven age-matched controls.

Total neutral lipids

49.5 i 1.0

65.6 i 0.7

Free fatty acids

12.6 i 1.5

27.4 i 2.4

Mono- and diacylglycerols

2.3 i 0.1

6.4 i 1.0

Triacylglycerols

11.9 i 0.6

12.0 i 3.2

Fatty acid esters

3.3 i 0.2

4.8 i 0.4

Cholesterol

8.0 i 0.4

5.9 i 0.7

Cholesteryl esters

6.8 i 0.6

5.9 i 0.6

Undetermined

5.3 i 0.4

3.2 i 0.4

Phospolipids

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