Fatty acids mobilization

Nicotinic acid decreases formation and secretion of VLDL by the liver (mechanism III in Fig. 23.2). This action appears secondary to its ability to inhibit fatty acid mobilization from adipose tissue. Circulating free fatty acids provide the main source of fatty acids for hepatic... 

T Fatty acid mobilization (adipose tissue) T Ketogenesis... 

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (see p. 108), and activates pyruvate carboxylase (see p. 117). The oxaloacetate thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl Co A is channeled into ketone body synthesis. 

Certain pathological conditions can lead to a life-threatening rise in the blood levels of the ketone bodies. Most common of these conditions is diabetic ketosis in patients with insulin-dependent diabetes mellitus. The absence of insulin has two major biochemical consequences. First, the liver cannot absorb glucose and consequently cannot provide oxaloacetate to process fatty acid-derived acetyl CoA (Section 17.3.1). Second, insulin normally curtails fatty acid mobilization by adipose tissue. The liver thus produces large amounts of ketone bodies, which are moderately strong acids. The result is severe acidosis. The decrease in pH impairs tissue function, most importantly in the central nervous system. 

The nature of the fatty acids in TAGs determines their hydrophobicity/hydrophih-city and diffusional mobility. In an aqueous/hpid environment, such as adipose tissue or lipoproteins in plasma, the relative hydrophihcity of the TAGs determines their partitioning between the interfacial phase and the apolar phase. This may have far stretching consequences. For instance, the rate and selectivity of fatty acid mobilization from fat cells may affect levels and composition of the nonester-ified fatty acids in plasma. These in mrn affect lipid homeostasis. Rate and selectivity of fatty acid mobilization from adipose stores are not related to the positional distribution of fatty acids on the glycerol backbone (75). They are related, however, to triacylglycerol hydrophihcity and thus to TAG structure (76). 

After ingestion of food, a small rise in serum insulin suppresses effectively fatty acid mobilization from adipose tissue but has little effect on glucose transport. A single intravenous injection of insulin does not decrease serum triglycerides. However, small amounts of insulin infused for a number of hours result in significant reduction, leading finally to an increase in insulin... 

The results obtained were not predictable based on the pharmacological and endocrinological literature derived from experiments on mammals. The case of GEM best illustrates this point. In mammals, it is well known that GH stimulates fatty acids mobilization from the liver. In turn, fatty acids feedback negatively on GH release46. By lowering circulating fatty acid levels with GEM in fish, it was predicted that GH mRNA levels and/or serum GH levels would increase. We observed a decrease in GH mRNA and no effects of GEM on serum GH. 

D. Steinberg, Fatty acid mobilization -mechanisms of regulation and metabolic consequence, Biochem. Soc. Symp., 1963, 24, 111-138. 

The role of perlipin A in fatty acid mobilization (Chapter 22)... 

In patients with cancer, weight loss indicates a poor prognosis and a shorter survival time. Cancer cachexia involves a massive loss of body weight, with extensive breakdown of both body fat and skeletal muscle, often, but not always, accompanied by anorexia (DeWys, 1985). Metabolic studies have shown that increased free fatty acid mobilization... 

High blood glucose elicits the release of insulin, which speeds the uptake of glucose by tissues and favors the storage of fuels as glycogen and triacylglycerols, while inhibiting fatty acid mobilization in adipose tissue. 

Fatty acids mobilized from adipose tissne are the major sonrce of energy for most tissues. Because he is eating, and not in total starvation, his ketone bodies were only moderately elevated in the blood (110 p,M vs. normal of 70 p,M) and did not appear in the urine. 

Fatty acids for VLDL synthesis in the liver may be obtained from the blood or they may be synthesized from glucose. In a healthy individual, the major source of the fatty acids of VLDL triacylglycerol is excess dietary glucose. In individuals with diabetes mellitus, fatty acids mobilized from adipose triacylglycerols in excess of the oxidative capacity of tissues are a major source of the fatty acids re-esterified in liver to VLDL triacylglycerol. These individuals frequently have elevated levels of blood triacylglycerols. 

A short feedback loop also links insulin stores to fatty acid. Insulin inhibits free fatty acid mobilization and elevation of fatty acid levels in plasma, stimulates insulin release. 

Epinephrine, injected in vivo, exerts an effect on adipose tissue, which can still be revealed by the increased fatty acid mobilizing activity of the tissue, examined in vitro (Reshef and Shapiro 1960). No increased release could be demonstrated in tissues of adrenalectomized animals, injected with epinephrine. Cortisone was also required to obtain this effect. The interdependance of epinephrine and cortical hormones was also shown in experiments in vivo. The elevation of plasma free fatty acids in dogs injected with epinephrine was abolished by adrenalectoncy or by hypophyzectomy (Shafrir, Sussman and Steinberg 1960). 

Steinberg, D. Fatty acid mobilization-mechanisms of regulation and metabolic consequences — p. Ill—138. In J. K. Grant The Control of Lipid Metabolism. London Academic Press 1963. 

My first experiments with pancreatectomized ducks gave results which were basically in agreement with those reported by Miahle and in view of the limited information about the effect of glucagon on the serum lipids of birds available at the time, I turned my attention to this question. It was then observed that injection of glucagon caused a marked and rapid elevation of plasma FFA in all of the avian species examined and this prompted a study of the effects in birds of other hormones known to affect fatty acid mobilization in mammals. 

The evidence at hand suggests that glucagon is the main hormonal factor controlling fatty acid mobilization in birds, and perhaps in some mammals. It seems also evident that insulin is not antilipolytic in birds. Thus the elevation of plasma FFA induced by fasting in the bird, which we have observed, can not be ascribed to decrease of insulin secretion, and is likely to be due to increased production of glucagon. The importance of glucagon for the control of fat mobilization in birds is illustrated by the fact that pancreatectomy... 

Grande, F. (1969). Lack of insulin effect on free fatty acid mobilization produced by glucagon in birds. Proc. Soc. Exptl. Biol. Med. 130, 711. 

Packham, D. E. Jiang, L. Conigrave, A. D. Arachidonate and other fatty acids mobilize Ca ions and stimulate beta-glucuronidase release in a Ca (2 -I- )-dependent fashion from undifferentiated HL-60 cells. Cell Calcium 1995,17, 399-408. 

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