De novo lipogenesis in humans: metabolic and regulatory aspects

Hellerstein, M. K.

doi:10.1038/sj.ejcn.1600744

Cited by 199 publications

(152 citation statements)

References 81 publications

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“…Furthermore, protein levels of FAS and SCD were increased in livers of apoB/BATless mice. Lipogenesis is a modest but significant source of TG for VLDL secretion in rodents (33,43) and in humans with obesity and insulin resistance (44,45). Studies from the laboratory of Goldstein and Brown have characterized in detail the role of the basic/ helix-loop-helix/leucine zipper transcription factor, SREBP1c, in the regulation of hepatic lipogenesis (8).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

Zhang

Hernandez‐Ono

Siri

et al. 2006

Journal of Biological Chemistry

144

110

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Insulin-resistant apoB/BATless mice have hypertriglyceridemia because of increased assembly and secretion of very low density apolipoprotein B (apoB) and triglycerides compared with mice expressing only apoB (Siri, P., Candela, N., Ko, C., Zhang, Y., Eusufzai, S., Ginsberg, H. N., and Huang, L. S. (2001) J. Biol. Chem. 276, 46064 -46072). Despite increased very low density lipoprotein secretion, apoB/BATless mice have fatty livers. We found that hepatic mRNA levels of key lipogenic enzymes, acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase-1 were increased in apoB/BATless mice compared with levels in apoB mice, suggesting increased lipogenesis in apoB/BATless mice. This was confirmed by determining incorporation of tritiated water into fatty acids. Neither the hepatic mRNA of the lipogenic transcription factor, SREBP-1c (sterol-response element-binding protein 1c), nor the nuclear levels of the mature form of SREBP-1 protein were elevated in apoB/BATless mice. By contrast, hepatic levels of peroxisomal proliferator-activated receptor 2 (PPAR␥2) mRNA and protein were specifically increased in apoB/BATless mice, as were hepatic mRNA levels of two targets of PPAR␥, CD36 and aP2. Treatment of apoB/BATless mice for 4 weeks with intraperitoneal injections of a PPAR␥ antisense oligonucleotide resulted in dramatic reductions of both PPAR␥1 and PPAR␥2 mRNA, PPAR␥2 protein, and mRNA levels of fatty-acid synthase and acetyl-CoA carboxylase. These changes were associated with decreased hepatic de novo lipogenesis and hepatic triglyceride concentrations. We conclude that hepatic steatosis in apoB/ BATless mice is associated with elevated rates of hepatic lipogenesis that are linked directly to increased hepatic expression of PPAR␥2. The mechanism whereby hepatic Ppar␥2 gene expression is increased and how PPAR␥2 stimulates lipogenesis is under investigation.We reported previously that apoB/BATless mice, a model generated by crossing mice expressing human apolipoprotein B (apoB) 3 (1) with mice lacking brown adipose tissue (BATless) (2), have hypertriglyceridemia and hypercholesterolemia because of a 2-3-fold increase in the secretion of very low density lipoprotein (VLDL) apoB and triglycerides (TG) relative to mice expressing apoB only (3). Similar levels of apoB mRNA in the livers of apoB and apoB/BATless mice indicated that the differences in apoB secretion resulted from differences in posttranscriptional regulation of VLDL assembly and secretion (4). There were no differences in hepatic levels of microsomal triglyceride transfer protein mRNA (3), a critical factor in the early co-and post-translational regulation of apoB-containing lipoprotein secretion (5). Low density lipoprotein receptor mRNA levels in liver were higher in apoB/BATless compared with apoB mice (3), indicating that increased apoB secretion in apoB/BATless mice did not result from reduced interactions of the low density lipoprotein receptor with nascent apoB lipoproteins (6).Associated with a rising prevalence of obesity and insuli...

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Section: Discussionmentioning

confidence: 99%

Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

Zhang

Hernandez‐Ono

Siri

et al. 2006

Journal of Biological Chemistry

144

110

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“…In the late 20th century, a novel isotopic method called 'mass isotopomer distribution analysis' (MIDA) had been developed by Hellerstein's group [11][12][13] to assess hepatic DNL, It should, however, be borne in mind that, in order to quantitatively evaluate adipose tissue DNL, the incorporation of label in adipose tissue during short-term administration of labeled precursors is generally too short, due to the slow turnover of adipose tissue triglycerides. Therefore, monitoring tracer incorporation into adipose tissue lipids might be impractical due to the huge dilution of the tracer in the large adipose triglyceride pool.…”

Section: How Is Dnl Estimated?mentioning

confidence: 99%

“…19 When saturation of glycogen stores occurs the diversion of excess CHO into fat will be operating as a virtual 'sink' process or a sort of safety valve. 12 It is necessary to dispose of the excessive exogenous CHO, since this is limited by the magnitude of the oxidation process in the tissues consuming glucose.…”

Section: Fat Balance and De Novo Lipogenesis Y Schutzmentioning

confidence: 99%

Concept of fat balance in human obesity revisited with particular reference to de novo lipogenesis

Schütz

2004

Int J Obes

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The measurement of fat balance (fat input minus fat output) involves the accurate estimation of both metabolizable fat intake and total fat oxidation. This is possible mostly under laboratory conditions and not yet in free-living conditions. In the latter situation, net fat retention/mobilization can be estimated based on precise and accurate sequential body composition measurements. In case of positive balance, lipids stored in adipose tissue can originate from dietary (exogenous) lipids or from nonlipid precursors, mainly from carbohydrates (CHOs) but also from ethanol, through a process known as de novo lipogenesis (DNL). Basic equations are provided in this review to facilitate the interpretation of the different subcomponents of fat balance (endogenous vs exogenous) under different nutritional circumstances. One difficulty is methodological: total DNL is difficult to measure quantitatively in man; for example, indirect calorimetry only tracks net DNL, not total DNL. Although the numerous factors (mostly exogenous) influencing DNL have been studied, in particular the effect of CHO overfeeding, there is little information on the rate of DNL in habitual conditions of life, that is, large day-to-day fluctuations of CHO intakes, different types of CHO ingested with different glycemic indexes, alcohol combined with excess CHO intakes, etc. Three issues, which are still controversial today, will be addressed: (1) Is the increase of fat mass induced by CHO overfeeding explained by DNL only, or by decreased endogenous fat oxidation, or both? (2) Is DNL different in overweight and obese individuals as compared to their lean counterparts? (3) Does DNL occur both in the liver and in adipose tissue? Recent studies have demonstrated that acute CHO overfeeding influences adipose tissue lipogenic gene expression and that CHO may stimulate DNL in skeletal muscles, at least in vitro. The role of DNL and its importance in health and disease remain to be further clarified, in particular the putative effect of DNL on the control of energy intake and energy expenditure, as well as the occurrence of DNL in other tissues (such as in myocytes) in addition to hepatocytes and adipocytes.

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“…Fat overfeeding, on the other hand, has little effect on substrate oxidation, so that net energy storage is greater (Horton et al 1995). Moreover, there is strong evidence that de novo lipogenesis is quantitatively an insignificant pathway in human subjects under normal Western diet conditions (Acheson et al 1988;Hellerstein, 1999). De novo lipogenesis is only invoked when carbohydrate overfeeding is massive (Acheson et al 1988).…”

Section: Reducing Consumption Of Fatty Foodsmentioning

confidence: 99%

Role of dietary carbohydrate and frequent eating in body-weight control

Kirk

2000

Proc. Nutr. Soc.

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Despite widespread interest in body-weight control, the prevalence of obesity continues to rise worldwide. Current public health advice for obesity prevention is clearly failing. The present paper examines the appropriateness of current public health advice for body-weight control, i.e. to reduce consumption of fatty foods, to reduce consumption of sugar and to avoid snacking between meals. An increase in carbohydrate : fat ratio should improve body-weight control, as high-carbohydrate low-fat diets are less likely to lead to overeating, and if overeating does occur, less of the excess energy is likely to be stored as fat. However, it is suggested that for the long-term prevention of weight gain, advice to increase consumption of carbohydrate-rich foods may be more effective than advice which focuses on reducing consumption of fatty food. Moreover, in view of the inverse relationship between fat and sugar intakes, sugar may have a positive role to play in body-weight control in facilitating an increase in carbohydrate : fat ratio. Snacking for most individuals appears not to adversely affect body-weight control, and for some it may improve control. This situation may exist because frequent eating helps appetite control, thus preventing overeating at meals, and as snacks overall tend to be higher in carbohydrate and lower in fat than meals, frequent eating may be a strategy for increasing carbohydrate : fat ratio. It is also suggested that eating ‘little and often’ may be a more compatible pattern of eating for a physically-active lifestyle than eating large meals. Perhaps the most appropriate advice on food intake that would work synergistically with concurrent advice to increase physical activity is to eat more carbohydrate, and to eat frequently.

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De novo lipogenesis in humans: metabolic and regulatory aspects

Cited by 199 publications

References 81 publications

Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

Aberrant Hepatic Expression of PPARγ2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis

Concept of fat balance in human obesity revisited with particular reference to de novo lipogenesis

Role of dietary carbohydrate and frequent eating in body-weight control

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