Fatty-Acid Biosynthesis in Man, a Pathway of Minor Importance. Purification, Optimal Assay Conditions, and Organ Distribution of Fatty-Acid Synthase

Weiss, Ludwig; Hoffmann, Georg; Schreiber, Rolf; Andres, Herbert; Fuchs, Edith; Körber, Elisabeth; Kolb, Helmut J.

doi:10.1515/bchm3.1986.367.2.905

Cited by 168 publications

(123 citation statements)

References 13 publications

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“…Calculated synthesis rate of palmitate or total non-essential FA based on¯ux through the circulating VLDL-TG pool is`1 ± 2 gad, a small amount compared to the 50 ± 150 g fat in the diet each day. These results con®rm prior conclusions from indirect calorimetry (Tappy et al, 1995; Acheson et al, De novo lipogenesis in humans MK Hellerstein 1982, comparisons of tissue to diet FA composition, and in vitro enzyme measurements (Shrago et al, 1971;Weiss et al, 1986;Sjostrom, 1973) (discussed above). The initial studies were performed in healthy men who were non-obese, non-diabetic, and on high-fat, eucaloric diets in the absence of potential lipogenic stimulators such Figure 1A Schematic model of polymerization biosynthesis.…”

Section: Regulation Of Dnl In Humanssupporting

confidence: 87%

“…Most studies (Shrago et al, 1971;Weiss et al, 1986;Sjo Èstrom, 1973;Askanazi et al, 1980) have reported quite low maximal lipogenic rates in human lipogenic tissues compared to rodents, for example (Table 2). These studies might underestimate capacity for inducing DNL, however, since most subjects were studied under typical high-fat eucaloric conditions.…”

Section: Enzyme Activities In Tissuesmentioning

confidence: 99%

“…Although most work has focused on hepatic DNL in humans and enzyme levels have suggested adipose to be a weakly lipogenic tissue in people (Shrago et al, 1971;Weiss et al, 1986;Sjostrom, 1973), recent evidence (Aarsland et al, 1996) suggests that adipose tissue may be the place to look for quantitatively signi®cant DNL during overfeeding, particularly by the parenteral route. Before adipose DNL can be measured in vivo, however, two technical problems will need to be solved.…”

Section: What Is the Contribution Of Adipose Dnl In Humans?mentioning

confidence: 99%

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De novo lipogenesis in humans: metabolic and regulatory aspects

1999

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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. IntroductionIn 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

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Section: Regulation Of Dnl In Humanssupporting

confidence: 87%

Section: Enzyme Activities In Tissuesmentioning

confidence: 99%

Section: What Is the Contribution Of Adipose Dnl In Humans?mentioning

confidence: 99%

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De novo lipogenesis in humans: metabolic and regulatory aspects

1999

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“…Therefore, the levels of FAS in most tissues are low. In human tissue, FAS is distributed in cells involved in lipid metabolism and in hormone-sensitive cells, such as adipocytes, hepatocytes, sebaceous glands, and type II alveolar cells (Weiss et al, 1986). High FAS activity was observed in foetal brain tissue and gradually declined following aging (Salles et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Fatty acid synthase: a novel target for antiglioma therapy

et al. 2006

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High levels of fatty acid synthase (FAS) expression have been observed in several cancers, including breast, prostate, colon and lung carcinoma, compared with their respective normal tissue. We present data that show high levels of FAS protein in human and rat glioma cell lines and human glioma tissue samples, as compared to normal rat astrocytes and normal human brain. Incubating glioma cells with the FAS inhibitor cerulenin decreased endogenous fatty acid synthesis by approximately 50%. Cell cycle analysis demonstrated a time-and dose-dependent increase in S-phase cell arrest following cerulenin treatment for 24 h. Further, treatment with cerulenin resulted in time-and dose-dependent decreases in glioma cell viability, as well as reduced clonogenic survival. Increased apoptotic cell death and PARP cleavage were observed in U251 and SNB-19 cells treated with cerulenin, which was independent of the death receptor pathway. Overexpressing Bcl-2 inhibited cerulenin-mediated cell death. In contrast, primary rat astrocytes appeared unaffected. Finally, RNAi-mediated knockdown of FAS leading to reduced FAS enzymatic activity was associated with decreased glioma cell viability. These findings suggest that FAS might be a novel target for antiglioma therapy.

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“…Thus, it seems that AMPK activation plays a substantial role in the mechanism, whereby FAS inhibition induces cytotoxicity. As high levels of FAS expression occur commonly in human cancers, but only in a limited number of human tissues, 45 FAS inhibition may selectively activate AMPK in cancer cells whereas sparing most human tissues.…”

Section: Selective Ampk Activationmentioning

confidence: 99%

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Kuhajda

2008

Int J Obes

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AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, act to both monitor and restore cellular energy in response to energy depletion. Studied extensively in liver and skeletal muscle, AMPK is phosphorylated and activated by LKB1 in response to increasing AMP/ATP ratios, which occur in a variety of settings including hypoxia, nutrient starvation and redox imbalance. Interest in the roles of both AMPK and LKB1 in cancer has grown substantially, following the identification of LKB1 as the tumor suppressor gene mutated in the Peutz-Jegher familial cancer syndrome. Patients with the Peutz-Jegher syndrome harbor a single inactive LKB1 gene, and acquisition of a second inactivating lesion (loss of heterozygosity) leads to the development of the cancer in a variety of organs. Thus, the loss of AMPK activation is hypothesized to promote the development of malignancy. Conversely, pharmacological AMPK activation has recently been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft and mouse cancer allografts. Previously, changes in cell metabolism that accompanied the malignant phenotype have largely been considered a consequence of cellular transformation. Now, AMPK and energy metabolism are linked to the development and maintenance of the malignant phenotype. These findings have led to renewed interest in AMPK and cancer cell metabolism in general as potential targets for cancer therapy.

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Fatty-Acid Biosynthesis in Man, a Pathway of Minor Importance. Purification, Optimal Assay Conditions, and Organ Distribution of Fatty-Acid Synthase

Cited by 168 publications

References 13 publications

De novo lipogenesis in humans: metabolic and regulatory aspects

De novo lipogenesis in humans: metabolic and regulatory aspects

Fatty acid synthase: a novel target for antiglioma therapy

AMP-activated protein kinase and human cancer: cancer metabolism revisited

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