Lipogenesis impairment

Vestri, H., Maianu, L., Moellering, D., Garvey, W. (2007). Atypical antipsychotic drugs directly impair insulin action in adipocytes Effects on glucose transport, lipogenesis, and antilipolysis. Neuropsychopharmacology, 32, 765-772. 

There are no unequivocal reports of acetyl CoA carboxylase deficiency presumably impairment of this key enzyme in lipogenesis would not be compatible with intrauterine development. 

The activities of biotin-dependent carboxylases fall in deficiency, resulting in impaired gluconeogenesis, with accumulation of lactate, pyruvate, and alanine, and impaired lipogenesis, with accumulation of acetyl CoA, resulting in ketosis. There are also changes in the fatty acid composition of membrane lipids. A variety of abnormal organic acids are excreted by bothbiotin-deficient patients and experimental animals (as shown in Table 11.1). 

SMAM-1 Avian (Ajinkya, 1985) Liver— size, congested, fatty, infiltrated with intranuclear inclusion bodies Kidney— size [ Size of bursae, thymus, spleen (Dhurandhar et al., 1990, 1992) Impaired liver function (Dhurandhar et al., 1992) Impaired lipogenesis (Dhurandhar eta/., 1992) Glucagons deficiency (Dhurandhar et al., 1992)... 

As shown in a Swedish cohort of healthy 50-year-old men with 20 years follow-up, proportion of 14 0 and 16 0 in serum cholesterol esters predicted the development of metabolic syndrome, independently of other metabolic and lifestyle factors [105]. Besides serum lipids, proportion of PA in adipose tissue is also related to insulin sensitivity. Unlikely 14 0 and 18 0, which were positively associated with insulin sensitivity, PA inversely correlated with insulin sensitivity in 59 healthy British men and women [134]. Since the authors excluded the effect of dietary intake for any of these SFA, they concluded that the reason is de novo lipogenesis in adipose tissue. In human skeletal muscle phospholipids, SFA [135,135] and especially PA [137] have been negatively associated with insulin sensitivity and Type 2 diabetes, [138] which could partly reflect dietary intake [139], In a Finnish cohort study of 4 years follow-up, impaired fasting glucose and Type 2 diabetes incidence were associated with serum nonesterified 16 0 levels, but were not associated with baseline dietary 16 0 intakes assessed from dietary records [140], Recently published prospective follow-up study showed that erythrocyte membrane fatty acids nominaly predict incident type 2 diabetes [141], In the American Atherosclerosis Risk in Commimities (ARIC) study, 2909 middle-aged men and women were followed for 9 years. The incidence of Type 2 diabetes was associated with total SFA levels of plasma cholesterol esters (also observed for 16 0 independently) and phospolipids (also for 16 0 and 18 0) [101]. In a more recent 4-year case-... 

Figure 11.10 Interactions between fatty acid synthesis and oxidation in liver. In the fed state malonyl-CoA levels are high. This allows rapid fatty acid synthesis and inhibits jS-oxidation by lowering carnitine acyltransferase I activity. If triacylglycerol synthesis is impaired then acyl-CoAs will feedback to inhibit acetyl-CoA carboxylase. In the fed state this does not normally happen and tri-acylglycerols are incorporated into very-low-density lipoprotein for export to extrahepatic tissues. Glucagon excess in fasting leads to a suppression of glycolysis, cessation of lipogenesis and activation of -oxidation and ketogenesis. Reproduced with permission from Annual Review of Biochemistry, 49, 1980 by Annual Reviews Inc.

Insulin deficiency impairs several steps in lipogenesis as a result of decreased penetration of glucose and utilization in glycolytic pathway with reduced formation of a-glycerophosphate, decreased pyruvate dehydrogenase and acetyl CoA carboxylase activities with reduced fatty acid chain initiation, decreased fatty acid synthetase activity. 

Many of these deficiency conditions in animals can be explained in terms of the role of TPP in the oxidative decarboxylation of pyruvic acid. On a thiamin-deficient diet animals accumulate pyruvic acid and its reduction product lactic acid in their tissues, which leads to muscular weakness. Nerve cells are particularly dependent on the utilisation of carbohydrate and for this reason a deficiency of the vitamin has a particularly serious effect on nervous tissue. Since acetyl coenzyme A is an important metabolite in the synthesis of fatty acids (see p. 220), lipogenesis is reduced. The pentose phosphate pathway is also impaired by a deficiency of thiamin but there is little effect on the activity of the citric acid cycle. 

The rate of breakdown of protein tissue is accelerated. Large quantities of ketone bodies are excreted as a result of impairment in lipogenesis. 

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