Kidney acetoacetate activation

The liver and to a lesser extent the kidneys, contain glucose 6-phosphatase, whereas muscle and the brain do not. Hence, muscle and the brain, in contrast with the liver, do not release glucose. Another key enzymatic difference is that the liver has little of the transferase needed to activate acetoacetate to acetoacetyl CoA. Consequently, acetoacetate and 3-hydroxybutyrate are exported by the liver for use by heart muscle, skeletal muscle, and the brain. 

A variety of thiokinases probably exist, but only a few of them have been identified. Acetic acid and butyryl thiokinase have been purified from a variety of sources, including yeast, liver, and muscle. These two enzymes differ in their specificity for the substrate. Acetic thiokinase catalyzes only the oxidation of propionic, acetic, and acrylic acids, but butyryl thiokinase activates fatty acids of chain lengths ranging from 4-to 12-carbon units. A third thiokinase was also discovered. It acts on fatty acid chains with 5- to 22-carbon units and is found in the microsomes. This intracellular distribution is in striking contrast with the cellular location of all other enzymes involved in fatty acid oxidation, which are all in mitochondria. The palmityl enzyme, which is active in the presence of ATP and CoA, becomes inactive when incubated in the absence of CoA therefore, it has been proposed that the active form of the enzyme involves the formation of an enzyme-CoA complex. The heart, the skeletal muscle, and the kidney also contain a thiokinase that specifically activates acetoacetic acid. Acetoacetic acid thiokinase is absent in liver this observation is significant in the pathogenesis of ketosis. 

The liver is clearly well equipped to utilize free fatty acids and to interconvert acetoacetate and hydroxybutyrate, but the virtual absence of 3-Oxoacid-CoA transferase and lipoprotein lipase means that any significant uptake of ketone bodies and triglycerides is restricted to extra-hepatic tissues. Heart and kidney contain the necessary enzymes to deal with all four fuels and this may reflect their high metabolic activity. Page and Williamson (1971) have shown that normal human brain has the capacity to utilize ketone bodies. 

Fatty acid oxidation can be terminated in either of two ways. Acetoacetyl CoA can either be cleaved to two molecules of acetyl CoA which condense with oxalacetate to form citrate, or it can be deacylated to acetoacetate by a deacylase specific for d-keto butyryl CoA. - In kidney and heart muscle there is no accumulation of acetoacetate, whereas in liver acetoacetate is formed in preference to citrate. The non-accumulation of acetoacetate in tissues other than liver probably is referable to the following circumstances. All tissues but liver contain activating enzymes which catalyze the conversion of acetoacetate to acetoacetyl CoA. Thus any acetoacetate formed by deacylation is thrust back as it were into the metabolic wheel. In liver deacylation is not opposed by this reactivation of acetoacetate. Hence acetoacetate accumulates only in liver. 

Both kidney and heart mitochondria contain enzymes which catalyze respectively the activation of acetate and acetoacetate by a... 

Examination of tissues post mortem showed normal acetoacetate oxidation by muscle and normal ketogenesis in liver. The severity of ketosis eliminated non-metabolic causes such as starvation and salicylism, and further investigation of post-mortem tissues for acetoacetyl-CoA thiolase, 3-hydroxybutyrate dehydrogenase and succinyl-CoA 3-keto acid-CoA transferase activities revealed grossly deficient activity of the latter enzyme in brain, kidney, muscle and cultured fibroblasts, in the presence of normal activities of the other enzymes. 

A second case was reported briefiy with a slightly different presentation at 7 months of age in a family in which two siblings had died earlier at 6 months. Blood 3-hydroxybutyrate and acetoacetate concentrations were 29 and 1.3 mmol 1 respectively during acidotic periods and less than 0.2 during symptom-free periods. Liver 3-hydroxybutyrate dehydrogenase activity and kidney, brain and cultured fibroblast acetoacetyl-CoA thiolase activities were normal, but succinyl-CoA 3-keto acid-CoA transferase activity was absent from these tissues (Spence et aL, 1973). However, no detailed report has yet appeared to substantiate these observations. 

---