De novo lipogenesis in humans: metabolic and regulatory aspects

European Journal of Clinical Nutrition (1999) 53, Suppl 1, S53±S65 ß 1999 Stockton Press. All rights reserved 0954±3007/99 $12.00 http://www.stockton-press.co.uk/ejcn De novo lipogenesis in humans: metabolic and regulatory aspects MK Hellerstein1* 1 Department of Nutritional Sciences, University of California at Berkeley, Berkeley, CA 94270-3104, USA The enzymatic pathway for converting dietary carbohydrate (CHO) into fat, or de novo lipogenesis (DNL), is present in humans, whereas the capacity to convert fats into CHO does not exist. Here, the quantitative importance of DNL in humans is reviewed, focusing on the response to increased intake of dietary CHO. Eucaloric replacement of dietary fat by CHO does not induce hepatic DNL to any substantial degree. Similarly, addition of CHO to a mixed diet does not increase hepatic DNL to quantitatively important levels, as long as CHO energy intake remains less than total energy expenditure (TEE). Instead, dietary CHO replaces fat in the whole-body fuel mixture, even in the post-absorptive state. Body fat is thereby accrued, but the pathway of DNL is not traversed; instead, a coordinated set of metabolic adaptations, including resistance of hepatic glucose production to suppression by insulin, occurs that allows CHO oxidation to increase and match CHO intake. Only when CHO energy intake exceeds TEE does DNL in liver or adipose tissue contribute signi®cantly to the wholebody energy economy. It is concluded that DNL is not the pathway of ®rst resort for added dietary CHO, in humans. Under most dietary conditions, the two major macronutrient energy sources (CHO and fat) are therefore not interconvertible currencies; CHO and fat have independent, though interacting, economies and independent regulation. The metabolic mechanisms and physiologic implications of the functional block between CHO and fat in humans are discussed, but require further investigation. Introduction In this review, I will address the fate of surplus dietary carbohydrate (CHO) in humans. More speci®cally, the focus will be on conversion of CHO to fat, or de novo lipogenesis (DNL), with the question framed in quantitative terms: to what extent is surplus dietary CHO energy converted to fat? The various ways in which CHO content of the diet can be increased will be considered: increased CHO that replaces dietary fat (high-CHO low-fat, eucaloric diets); CHO added to a mixed diet, where CHO energy is less than total energy expenditure (TEE) but total energy intake exceeds TEE; and CHO consumption in excess of TEE. This review will therefore focus on the upper limits and consequences of increased CHO intake rather than on the lower limits and consequences of insuf®cient fat intake. Background and historical review The enzymatic pathway of DNL is present in all organisms. Knowledge concerning the genes and enzymes of DNL and their regulation has advanced considerably (reviewed in Bloch, 1977; Girard et al, 1994; Sul et al, 1993). Nevertheless, quantitative and regulatory aspects of DNL in metabolic physiology remain controversial. It has been widely presumed that DNL functions primarily as a sink for storage of excess CHO energy and to a lesser extent for the synthesis of structural, non-essential lipids (Table 1). Indeed, many animals are well known to convert CHO to fat (Lawes & Gilbert, 1886; Florkin & Stotz, 1977): pigs fatten on a grain diet, for example, and bees convert honey to wax. Although conversion of CHO to fat prior to *Correspondence: MK Hellerstein, Department of Nutritional Sciences, University of California at Berkeley, Berkeley, CA 94270-3104, USA. oxidation is believed to be thermogenically costly (using ca. 28% of the energy content of CHO, Flatt, 1978; Hellerstein et al, 1996), the pathway is known to have regulated steps and is therefore presumed to play a role in normal physiology. Despite considerable information about the regulation of acetyl-CoA carboxylase, fatty acyl synthetase, malonyl-CoA and other components of the enzymatic pathway (Bloch, 1977; Girard et al, 1994), the quantitative importance of DNL has remained an area of uncertainty until recently. Most of this uncertainty can be attributed to limitations in the methods available to address this question. Both indirect and direct techniques for measuring DNL have been used. Indirect approaches for assessing the role of DNL in humans A number of indirect approaches have been applied to this question. Comparison of fatty acid (FA) composition in adipose tissue and diet Over 30 y ago, Hirsch (1965) observed that adipose FA composition in human subjects closely resembled that of the Western diet. Individuals were also placed on conTable 1 Overview of de novo lipogenesis (DNL) as a pathway (A) Presumed functions of DNL in the organism:  Synthesis of structural lipids  Storage of surplus CHO energy as fat (B) High thermogenic costs (C) Enzymology and regulation of DNL:  Key regulatory node ˆ Acetyl-CoA carboxylase (ACC)  Malonyl-CoA as product of ACC and regulator of FA oxidation (D) Quantitative importance of DNL uncertain De novo lipogenesis in humans MK Hellerstein S54 1996; JeÂquier et al, 1987), it is clear that DNL within a biologic system will generate RQ > 1.0 and that RQ > 1.0 represents DNL. The major interpretative problem with indirect calorimetry in this regard is that it measures net DNL, not unidirectional ¯ux through the pathway. An NP RQ > 1.0 indicates only that synthesis is greater than oxidation of fat in the whole system during the period that is sampled. Lipogenesis from CHO in one tissue could be balanced by fat oxidation in another, for example, and the resultant RQ (1.0) would not be distinguishable from direct CHO oxidation (Tappy et al, 1995). Nevertheless, indirect calorimetry has provided useful information about the response to large CHO loads. A number of studies (Acheson et al, 1982, 1984; Hellerstein et al, 1991) have con®rmed that a single meal containing large amounts of CHO energy (up to 500 g CHO) in previously weight stable subjects does not cause NP RQ to rise above 1.0. This has been interpreted as evidence against a quantitatively important role for DNL in the dayto-day storage of surplus CHO energy; also, storage as glycogen was concluded to represent the fate of excess dietary CHO. Several days of surplus energy intake as CHO (Schwarz et al, 1995; Passmore and Swindells, 1963) also does not induce much net DNL (RQ reaches 0.98 ± 1.01). In contrast, studies of massive CHO overfeeding (6000 kcal=d; 1500 g CHO) performed by Acheson et al (1988) showed that after about three days, when a positive whole CHO balance of 800 g had occurred, RQ rose well above 1.0; these investigators calculated that maximal whole-body glycogen storage capacity was ca. 700 ± 1000 g and needed to be exceeded before net DNL became signi®cant, after which time substantial net DNL occurred (for example, 150 g=d net fat synthesis after seven days of overfeeding) (...truncated)