Ketone bodies liver production

While an active enzymatic mechanism produces acetoacetate from acetoacetyl-CoA in the liver, acetoacetate once formed cannot be reactivated directly except in the cytosol, where it is used in a much less active pathway as a precursor in cholesterol synthesis. This accounts for the net production of ketone bodies by the liver. 

In most cases, ketonemia is due to increased production of ketone bodies by the liver rather than to a deficiency in their utilization by extrahepatic tissues. While acetoacetate and d(—)-3-hydroxybutyrate are readily oxidized by extrahepatic tissues, acetone is difficult to oxidize in vivo and to a large extent is volatilized in the lungs. 

Starvation elicits mobilization of triglycerides from the adipose tissue and inhibits the endogenic cholesterol synthesis owing to the low activity of hydroxy-methylglutaryl-CoA reductase. The latter process provides the possibility for the active production of ketone bodies in the liver. 

Medium-chain acyl-CoA synthetase, which is present within the mitochondrial matrix of the liver, activates fatty acids containing from four to ten carbon atoms. Medium-chain length fatty acids are obtained mainly from triacylglycerols in dairy products. However, unlike long-chain fatty acids, they are not esterified in the epithelial cells of the intestine but enter the hepatic portal vein as fatty acids to be transported to the liver. Within the liver, they enter the mitochondria directly, where they are converted to acyl-CoA, which can be fully oxidised and/or converted into ketone bodies. The latter are released and can be taken up and oxidised by tissues. 

The increased oxidation of fatty acids decreases the rate of glucose utilisation and oxidation by muscle, via the glucose/fatty acid cycle, which accounts for some of the insulin resistance in trauma. An additional factor may be the effect of cytokines on the insulin-signalling pathway in muscle. An increased rate of fatty acid oxidation in the liver increases the rate of ketone body production the ketones will be oxidised by the heart and skeletal muscle, which will further reduce glucose utilisation. This helps to conserve glucose for the immune and other cells. 

The liver is the most important site for the formation of fatty acids, fats (triacylglycewls), ketone bodies, and cholesterol. Most of these products are released into the blood, in contrast, the triacylglycerols synthesized in adipose tissue are also stored there. 

If the production of ketone bodies exceeds the demand for them outside the liver, there is an increase in the concentration of ketone bodies in the plasma (ketonemia) and they are also eventually excreted in the urine (ketonu-ria). Both phenomena are observed after prolonged starvation and in inadequately treated diabetes mellitus. Severe ketonuria with ketoacidosis can cause electrolyte shifts and loss of consciousness, and is therefore life-threatening (ketoacidotic coma). 

A. Ketone body synthesis (ketogenesis) occurs only in the mitochondria of liver cells when acetyl CoA levels exceed the needs of the organ for use in energy production. 

Ketone bodies (KBs) circulate in the blood as (CH3-CHOH-CH2-COOH) and ACAC (CH3-CO-CH2-COOH). The blood concentrations of these two metabolites depend upon the equilibrium between their production by the liver (ketogen-esis) and consumption at the peripheral level (ketogenolysis). Abnormalities of KB metabolism manifest as ketosis, hypoketotic hypoglycaemia and inversion of the 30HB arachidonic acid (AA) ratio [12]. 

The production and export of ketone bodies by the liver allow continued oxidation of fatty acids with only minimal oxidation of acetyl-CoA When intermediates of the citric acid cycle are being siphoned off for glucose... 

The first two reactions in the cholesterol synthetic pathway are siri lar to those in the pathway that produces ketone bodies (see Figure 16.22, p. 194). They result in the production of 3-hydroxy-3-methyl-glutaryl CoA (HMG CoA, Figure 18.3). First, two acetyl CtA molecules condense to form acetoacetyl CoA. Next, a third molecule of acetyl CoA is added, producing HMG CoA, a six-carbon compound. [Note Liver parenchymal cells contain two isoenzymes of HMG CoA synthase. The cytosolic enzyme participates in cholesterol synthesis, whereas the mitochondrial enzyme Urc tions in the pathway for ketone body synthesis.]... 

Ketone bodies (acetoacetate, /3-hydroxybutyrate, and acetone structures are presented in fig. 18.7) are made in the liver when /3 oxidation of fatty acids is in excess of that required by the liver. These water-soluble, energy-rich compounds are transported to other tissues for generation of energy. As we discuss later on, excess production of ketone bodies, that occurs during starvation or untreated diabetes, can be harmful. 

In this section we have seen that fatty acids are oxidized in units of two carbon atoms. The immediate end products of this oxidation are FADH2 and NADH, which supply energy through the respiratory chain, and acetyl-CoA, which has multiple possible uses in addition to the generation of energy via the tricarboxylic acid cycle and respiratory chain. Unsaturated fatty acids can also be oxidized in the mitochondria with the help of auxiliary enzymes. Ketone body synthesis from acetyl-CoA is an important liver function for transfer of energy to other tissues, especially brain, when glucose levels are decreased as in diabetes or starvation. 

The main end product of fatty acid oxidation is acetyl-CoA, which can be used by the tricarboxylic acid cycle for generation of energy. Alternatively, ketone bodies may be formed from condensation of acetyl-CoAs. Ketone bodies are made in the liver and subsequently diffuse into the blood to be carried to... 

Answer Individuals with uncontrolled diabetes oxidize large quantities of fat because they cannot use glucose efficiently. This leads to a decrease in activity of the citric acid cycle (see Problem 17) and an increase in the pool of acetyl-CoA. If acetyl-CoA were not converted to ketone bodies, the CoA pool would become depleted. Because the mitochondrial CoA pool is small, liver mitochondria recycle CoA by condensing two acetyl-CoA molecules to form acetoacetyl-CoA + CoA (see Fig. 17-18). The acetoacetyl-CoA is converted to other ketones, and the CoA is recycled for use in the /8-oxidation pathway and energy production. 

Because insulin normally inhibits lipolysis, a diabetic has an extensive lipolytic activity in the adipose tissue. As is seen in Table 21.4, plasma fatty acid concentrations become remarkably high. /3-Oxidation activity in the liver increases because of a low insulin/glucagon ratio, acetyl-CoA carboxylase is relatively inactive and acyl-CoA-camitine acyltransferase is derepressed. /3-Oxidation produces acetyl-CoA which in turn generates ketone bodies. Ketosis is perhaps the most prominent feature of diabetes mellitus. Table 21.5 compares ketone body production and utilization in fasting and in diabetic individuals. It may be seen that, whereas in the fasting state ketone body production is roughly equal to excretion plus utilization, in diabetes this is not so. Ketone bodies therefore accumulate in diabetic blood. 

Figure 32-5. P-oxidation and ketogenesis in the liver. The rate-limiting step in fatty acid oxidation and subsequent ketone body production is the activity of carnitine acyltrans-ferase I (CAT I).The activity of CAT I is inhibited by malonyl-CoA. Insulin deficiency results in inhibition of acetyl-CoA carboxylase, decreased levels of maloyl-CoA, and thus increased activity of CAT-I.Adapted from Foster and McGarry (1983).

A major factor in stinoulating ketone body production is increased availability of FTAs. An increased rate of FFA mobilisation from the adipose tissue, with the consequent increase in FFA levels in the liver, may be sufficient to enhance ketone body formation. Increased release of FFAs occurs when the glucagon/insulin ratio... 

A deficiency purely in pantothenic acid has probably never occurred, except in controlled studies. Persons suffering from severe malnutrition would be expected to be deficient in the vitamin. Studies with animals have shown that consumption of a diet deficient in the vitamin results in a loss of appetite, slow growth, skin lesions, ulceration of the intestines, weakness, and eventually death. Pantothenic acid deficiency also results in the production of gray fur in animals whose fur is colored. Biochemical studies with deficient animals have revealed severe decreases in pantothenic acid levels in a variety of tissues, but only moderate declines in the levels of coenzyme A in liver and kidney and maintenance of coenz)nne A levels in the brain (Smith et ah, 1987). Some striking defects in glycogen and ketone body metabolism have been noted in pantothenic acid-deficient animals. 

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