共查询到20条相似文献，搜索用时 24 毫秒
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Anne-Marie Lundsgaard Jacob B. Holm Kim A. Sjøberg Kirstine N. Bojsen-Møller Lene S. Myrmel Even Fjære Benjamin A.H. Jensen Trine S. Nicolaisen Janne R. Hingst Sine L. Hansen Sophia Doll Philip E. Geyer Atul S. Deshmukh Jens J. Holst Lise Madsen Karsten Kristiansen Jørgen F.P. Wojtaszewski Erik A. Richter Bente Kiens 《Cell metabolism》2019,29(1):50-63.e4
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Michael K. Pickens Jim S. Yan Raymond K. Ng Hisanobu Ogata James P. Grenert Carine Beysen Scott M. Turner Jacquelyn J. Maher 《Journal of lipid research》2009,50(10):2072-2082
Methionine-choline-deficient (MCD) diets cause steatohepatitis in rodents and are used to study the pathophysiology of fatty liver disease in human beings. The most widely used commercial MCD formulas not only lack methionine and choline but also contain excess sucrose and fat. The objective of this study was to determine whether dietary sucrose in the MCD formula plays a role in the pathogenesis of MCD-related liver disease. We prepared two custom MCD formulas, one containing sucrose as the principal carbohydrate and the other substituting sucrose with starch. Mice fed the sucrose-enriched formula developed typical features of MCD-related liver disease, including hepatic steatosis, hepatocellular apoptosis, alanine aminotransferase elevation, lipid peroxidation, and hepatic inflammation. In contrast, mice fed MCD-starch were significantly protected against liver injury. MCD-sucrose and MCD-starch mice displayed identical diet-related abnormalities in hepatic fatty acid uptake and triglyceride secretion. Hepatic de novo lipogenesis and triglyceride synthesis, however, were 2 times higher in MCD-sucrose mice than MCD-starch mice (P < 0.01). Hepatic lipid analysis revealed accumulation of excess saturated fatty acids in MCD-sucrose mice that correlated with hepatocellular injury. Overall, the results indicate that dietary sucrose is critical to the pathogenesis of MCD-mediated steatohepatitis. They suggest that saturated fatty acids, which are products of de novo lipogenesis, are mediators of hepatic toxicity in this model of liver disease. 相似文献
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Candice A. Allister Li-fen Liu Cindy A. Lamendola Colleen M. Craig Samuel W. Cushman Marc K. Hellerstein Tracey L. McLaughlin 《Journal of lipid research》2015,56(2):435-439
Indirect evidence suggests that impaired triglyceride storage in the subcutaneous fat depot contributes to the development of insulin resistance via lipotoxicity. We directly tested this hypothesis by measuring, in vivo, TG synthesis, de novo lipogenesis (DNL), adipocyte proliferation, and insulin suppression of lipolysis in subcutaneous adipose tissue of BMI-matched individuals classified as insulin resistant (IR) or insulin sensitive (IS). Nondiabetic, moderately obese subjects with BMI 25–35 kg/m2, classified as IR or IS by the modified insulin suppression test, consumed deuterated water (2H2O) for 4 weeks. Deuterium incorporation into glycerol, palmitate, and DNA indicated TG synthesis, DNL, and adipocyte proliferation, respectively. Net TG synthesis and DNL in adipose cells were significantly lower in IR as compared with IS subjects, whereas adipocyte proliferation did not differ significantly. Plasma FFAs measured during an insulin suppression test were 2.5-fold higher in IR subjects, indicating resistance to insulin suppression of lipolysis. Adipose TG synthesis correlated directly with DNL but not with proliferation. These results provide direct in vivo evidence for impaired TG storage in subcutaneous adipose tissue of IR as compared with IS. Relative inability to store TG in the subcutaneous depot may represent a mechanism contributing to the development of insulin resistance in the setting of obesity. 相似文献
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Maggie S. Burhans Matthew T. Flowers Kristin R. Harrington Laura M. Bond Chang-An Guo Rozalyn M. Anderson James M. Ntambi 《Journal of lipid research》2015,56(2):304-318
Hepatic steatosis is associated with detrimental metabolic phenotypes including enhanced risk for diabetes. Stearoyl-CoA desaturases (SCDs) catalyze the synthesis of MUFAs. In mice, genetic ablation of SCDs reduces hepatic de novo lipogenesis (DNL) and protects against diet-induced hepatic steatosis and adiposity. To understand the mechanism by which hepatic MUFA production influences adipose tissue stores, we created two liver-specific transgenic mouse models in the SCD1 knockout that express either human SCD5 or mouse SCD3, that synthesize oleate and palmitoleate, respectively. We demonstrate that hepatic de novo synthesized oleate, but not palmitoleate, stimulate hepatic lipid accumulation and adiposity, reversing the protective effect of the global SCD1 knockout under lipogenic conditions. Unexpectedly, the accumulation of hepatic lipid occurred without induction of the hepatic DNL program. Changes in hepatic lipid composition were reflected in plasma and in adipose tissue. Importantly, endogenously synthesized hepatic oleate was associated with suppressed DNL and fatty acid oxidation in white adipose tissue. Regression analysis revealed a strong correlation between adipose tissue lipid fuel utilization and hepatic and adipose tissue lipid storage. These data suggest an extrahepatic mechanism where endogenous hepatic oleate regulates lipid homeostasis in adipose tissues. 相似文献
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Robin D. Clugston Jason J. Yuen Yunying Hu Nada A. Abumrad Paul D. Berk Ira J. Goldberg William S. Blaner Li-Shin Huang 《Journal of lipid research》2014,55(2):239-246
CD36 is a scavenger receptor with multiple ligands and cellular functions, including facilitating cellular uptake of free fatty acids (FFAs). Chronic alcohol consumption increases hepatic CD36 expression, leading to the hypothesis that this promotes uptake of circulating FFAs, which then serve as a substrate for triglyceride (TG) synthesis and the development of alcoholic steatosis. We investigated this hypothesis in alcohol-fed wild-type and Cd36-deficient (Cd36−/−) mice using low-fat/high-carbohydrate Lieber-DeCarli liquid diets, positing that Cd36−/− mice would be resistant to alcoholic steatosis. Our data show that the livers of Cd36−/− mice are resistant to the lipogenic effect of consuming high-carbohydrate liquid diets. These mice also do not further develop alcoholic steatosis when chronically fed alcohol. Surprisingly, we did not detect an effect of alcohol or CD36 deficiency on hepatic FFA uptake; however, the lower baseline levels of hepatic TG in Cd36−/− mice fed a liquid diet were associated with decreased expression of genes in the de novo lipogenesis pathway and a lower rate of hepatic de novo lipogenesis. In conclusion, Cd36−/− mice are resistant to hepatic steatosis when fed a high-carbohydrate liquid diet, and they are also resistant to alcoholic steatosis. These studies highlight an important role for CD36 in hepatic lipid homeostasis that is not associated with hepatic fatty acid uptake. 相似文献
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Francis W. B. Sanders Julian L. Griffin 《Biological reviews of the Cambridge Philosophical Society》2016,91(2):452-468
Hepatic de novo lipogenesis (DNL) is the biochemical process of synthesising fatty acids from acetyl‐CoA subunits that are produced from a number of different pathways within the cell, most commonly carbohydrate catabolism. In addition to glucose which most commonly supplies carbon units for DNL, fructose is also a profoundly lipogenic substrate that can drive DNL, important when considering the increasing use of fructose in corn syrup as a sweetener. In the context of disease, DNL is thought to contribute to the pathogenesis of non‐alcoholic fatty liver disease, a common condition often associated with the metabolic syndrome and consequent insulin resistance. Whether DNL plays a significant role in the pathogenesis of insulin resistance is yet to be fully elucidated, but it may be that the prevalent products of this synthetic process induce some aspect of hepatic insulin resistance. 相似文献
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Kaori Minehira Vincent Bettschart Hubert Vidal Nathalie Vega Vronique Di Vetta Valentine Rey Philippe Schneiter Luc Tappy 《Obesity (Silver Spring, Md.)》2003,11(9):1096-1103
Objective: To evaluate the effect of a 4‐day carbohydrate overfeeding on whole body net de novo lipogenesis and on markers of de novo lipogenesis in subcutaneous adipose tissue of healthy lean humans. Research Methods and Procedures: Nine healthy lean volunteers (five men and four women) were studied after 4 days of either isocaloric feeding or carbohydrate overfeeding. On each occasion, they underwent a metabolic study during which their energy expenditure and net substrate oxidation rates (indirect calorimetry), and the fractional activity of the pentose‐phosphate pathway in subcutaneous adipose tissue (subcutaneous microdialysis with 1, 613C2, 6, 62H2 glucose) were assessed before and after administration of glucose. Adipose tissue biopsies were obtained at the end of the experiments to monitor mRNAs of key lipogenic enzymes. Results: Carbohydrate overfeeding increased basal and postglucose energy expenditure and net carbohydrate oxidation. Whole body net de novo lipogenesis after glucose loading was markedly increased at the expense of glycogen synthesis. Carbohydrate overfeeding also increased mRNA levels for the key lipogenic enzymes sterol regulatory element‐binding protein‐1c, acetyl‐CoA carboxylase, and fatty acid synthase. The fractional activity of adipose tissue pentose‐phosphate pathway was 17% to 22% and was not altered by carbohydrate overfeeding. Discussion: Carbohydrate overfeeding markedly increased net de novo lipogenesis at the expense of glycogen synthesis. An increase in mRNAs coding for key lipogenic enzymes suggests that de novo lipogenesis occurred, at least in part, in adipose tissue. The pentose‐phosphate pathway is active in adipose tissue of healthy humans, consistent with an active role of this tissue in de novo lipogenesis. 相似文献
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Cong Zhang Yuzhen Lu Yingying Song Liang Chen Junjie Hu Yan Meng Xin Chen Shan Li Guohua Zheng Zhenpeng Qiu 《Journal of cellular and molecular medicine》2022,26(14):3995
Mounting evidence indicates that hepatic de novo lipogenesis is a common abnormality in non‐alcoholic fatty liver disease (NAFLD) patients. We investigated whether a selective COX‐2 inhibitor, celecoxib, alleviates hepatic steatosis by targeting an Akt‐driven lipogenic pathway. We estimated the efficacy of celecoxib in a novel Akt‐driven NAFLD mouse model established via hydrodynamic transfection of activated forms of AKT and in fructose‐fed NAFLD mice that exhibited increased insulin‐independent hepatic lipogenesis. AKT‐transfected and insulin‐stimulated human hepatoma cells were used for the in vitro experiments. Haematoxylin and eosin staining, immunohistochemistry and immunoblotting were performed for mechanistic studies. The results revealed that celecoxib ameliorated hepatic steatosis in the AKT‐triggered NAFLD mice. Mechanistically, celecoxib effectively suppressed AKT/mTORC1 signalling and its downstream lipogenic cascade in the Akt‐driven NAFLD mice and in vitro. Furthermore, celecoxib had limited efficacy in alleviating hepatic lipid accumulation and showed no influence on lipogenic proteins associated with hepatic lipogenesis in fructose‐administered mice. This study suggests that celecoxib may be favourable for the treatment of NAFLD, especially in the subset with Akt‐triggered hepatic lipogenesis. 相似文献
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《Animal : an international journal of animal bioscience》2013,7(6):965-973
Divergent selection of chickens for low or high abdominal fat (AF) but similar BW at 63 days of age was undertaken in 1977. The selection programme was conducted over seven successive generations. The difference between lines was then maintained constant at about twice the AF in the fat line as in the lean line. The aims of the first studies on these divergent chicken lines were to describe the growth, body composition and reproductive performance in young and adult birds. The lines were then used to improve the understanding of the relationship between fatness and energy and protein metabolism in the liver, muscle and adipose tissues, as well as the regulation of such metabolism at hormonal, gene and hypothalamic levels. The effects on muscle energy metabolism in relation to meat quality parameters were also described. This paper reviews the main results obtained with these lines. 相似文献
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Susanne B. Votruba Richard L. Atkinson Dale A. Schoeller 《Obesity (Silver Spring, Md.)》2003,11(12):1509-1518
Objective: Higher levels of physical activity have been associated with body weight maintenance, but previous work in our laboratory suggests that this is not purely related to energy balance. We hypothesize that this may be related to the partitioning of dietary fat between oxidation and storage. Research Methods and Procedures: Healthy women (age 24 ± 1 years, BMI = 21.2 ± 0.4 kg/m2) were recruited to participate in rest (n = 10) or exercise sessions of light (n = 11), moderate (n = 10), and heavy (n = 7) exercise. All exercises (1250 kJ above rest) were performed on a stationary cycle inside of a whole‐body calorimeter. [1‐13C]oleate and [d31]palmitate were given in a liquid meal 30 minutes post‐exercise. An additional study was done with identical exercise sessions, but with administration of an oral dose of [1‐13C]acetate and [d3]acetate 30 minutes post‐exercise to determine label sequestration. Results: Cumulative oxidation of [1‐13C]oleate was significantly greater after light (45 ± 3%), moderate (54 ± 4%), and heavy (51 ± 4%) exercise than that with rest (33 ± 3%) (p = 0.0008). Cumulative oxidation of [d31]palmitate did not differ among trials (12 ± 2%, 14 ± 1%, 17 ± 2%, and 14 ± 2% for rest, light, moderate, and heavy, respectively; p = 0.30). Discussion: Exercise standardized for energy expenditure increases monounsaturated fat oxidation more than saturated fat oxidation and that the increase occurs regardless of intensity. Recommendations for physical activity for the purposes of weight control may be specific for dietary fat composition. 相似文献
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Li Che Maria G. Pilo Antonio Cigliano Gavinella Latte Maria M. Simile Silvia Ribback 《Cell cycle (Georgetown, Tex.)》2017,16(6):499-507
Hepatocellular carcinoma (HCC), the most frequent primary tumor of the liver, is an aggressive cancer type with limited treatment options. Cumulating evidence underlines a crucial role of aberrant lipid biosynthesis (a process known as de novo lipogenesis) along carcinogenesis. Previous studies showed that suppression of fatty acid synthase (FASN), the major enzyme responsible for de novo lipogenesis, is highly detrimental for the in vitro growth of HCC cell lines. To assess whether de novo lipogenesis is required for liver carcinogenesis, we have generated various mouse models of liver cancer by stably overexpressing candidate oncogenes in the mouse liver via hydrodynamic gene delivery. We found that overexpression of FASN in the mouse liver is unable to malignantly transform hepatocytes. However, genetic deletion of FASN totally suppresses hepatocarcinogenesis driven by AKT and AKT/c-Met protooncogenes in mice. On the other hand, liver tumor development is completely unaffected by FASN depletion in mice co-expressing β-catenin and c-Met. Our data indicate that tumors might be either addicted to or independent from de novo lipogenesis for their growth depending on the oncogenes involved. Additional investigation is required to unravel the molecular mechanisms whereby some oncogenes render cancer cells resistant to inhibition of de novo lipogenesis. 相似文献
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Minehira K Young SG Villanueva CJ Yetukuri L Oresic M Hellerstein MK Farese RV Horton JD Preitner F Thorens B Tappy L 《Journal of lipid research》2008,49(9):2038-2044
The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity. 相似文献
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《遗传学报》2022,49(4):364-376
The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety. Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical application. In the present study, we investigated the anti-diabetic effects of a functionalized gadofullerene (GF) using obese db/db and non-obese mouse model of type 2 diabete mellitus (MKR) mouse type 2 diabetes mellitus (T2DM) models. In both mouse models, the diabetic phenotypes, including hyperglycemia, impaired glucose tolerance, and insulin sensitivity, were ameliorated after two or four weeks of intraperitoneal administration of GF. GF lowered blood glucose levels in a dose-dependent manner. Importantly, the restored blood glucose levels could persist ten days after withdrawal of GF treatment. The hepatic AKT/GSK3β/FoxO1 pathway is shown to be the main target of GF for rebalancing gluconeogenesis and glycogen synthesis in vivo and in vitro. Furthermore, GF treatment significantly reduced weight gain of db/db mice with reduced hepatic fat storage by the inhibition of de novo lipogenesis through mTOR/S6K/SREBP1 pathway. Our data provide compelling evidence to support the promising application of GF for the treatment of T2DM. 相似文献
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Anne P. L. Jensen-Urstad Haowei Song Irfan J. Lodhi Katsuhiko Funai Li Yin Trey Coleman Clay F. Semenkovich 《Journal of lipid research》2013,54(7):1848-1859
Peroxisome proliferator-activated receptor (PPAR)α is a nuclear receptor that coordinates liver metabolism during fasting. Fatty acid synthase (FAS) is an enzyme that stores excess calories as fat during feeding, but it also activates hepatic PPARα by promoting synthesis of an endogenous ligand. Here we show that the mechanism underlying this paradoxical relationship involves the differential regulation of FAS in at least two distinct subcellular pools: cytoplasmic and membrane-associated. In mouse liver and cultured hepatoma cells, the ratio of cytoplasmic to membrane FAS-specific activity was increased with fasting, indicating higher cytoplasmic FAS activity under conditions associated with PPARα activation. This effect was due to a nutrient-dependent and compartment-selective covalent modification of FAS. Cytoplasmic FAS was preferentially phosphorylated during feeding or insulin treatment at Thr-1029 and Thr-1033, which flank a dehydratase domain catalytic residue. Mutating these sites to alanines promoted PPARα target gene expression. Rapamycin-induced inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1), a mediator of the feeding/insulin signal to induce lipogenesis, reduced FAS phosphorylation, increased cytoplasmic FAS enzyme activity, and increased PPARα target gene expression. Rapamycin-mediated induction of the same gene was abrogated with FAS knockdown. These findings suggest that hepatic FAS channels lipid synthesis through specific subcellular compartments that allow differential gene expression based on nutritional status. 相似文献
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