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Wei R, Deng D, Teng Y, Lu C, Luo Z, Abdulai M, Liu H, Xu H, Li L, Hu S, Hu J, Wei S, Zeng X, Han C. Study on the effect of different types of sugar on lipid deposition in goose fatty liver. Poult Sci 2022; 101:101729. [PMID: 35172237 PMCID: PMC8850742 DOI: 10.1016/j.psj.2022.101729] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 09/15/2021] [Accepted: 11/04/2021] [Indexed: 01/02/2023] Open
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Masetto Antunes M, Godoy G, Curi R, Vergílio Visentainer J, Barbosa Bazotte R. The Myristic Acid:Docosahexaenoic Acid Ratio Versus the n-6 Polyunsaturated Fatty Acid:n-3 Polyunsaturated Fatty Acid Ratio as Nonalcoholic Fatty Liver Disease Biomarkers. Metab Syndr Relat Disord 2021; 20:69-78. [PMID: 34813379 DOI: 10.1089/met.2021.0107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
It is well established that diets containing an increased omega-6 polyunsaturated fatty acid (n-6 PUFA) to omega-3 polyunsaturated fatty acid (n-3 PUFA) ratios are linked to inflammation and chronic diseases such as nonalcoholic fatty liver disease (NAFLD). However, the influence of an elevated n-6 PUFA:n-3 PUFA ratio in the tissues requires clarification. Herein, we identified primary experimental and clinical studies where it is possible to compare the performance of the myristic acid (Myr):docosahexaenoic acid (DHA) and n-6 PUFA:n-3 PUFA ratios in the liver and/or serum as potential NAFLD biomarkers. Articles were included if quantitative values of n-6 PUFA, n-3 PUFA, Myr, DHA, and information about liver inflammation or liver disease progression parameters were provided. Overall, most experimental (91.6%) and clinical studies (87.5%) reported higher Myr:DHA ratios associated with inflammation and/or NAFLD progression than the n-6 PUFA:n-3 PUFA ratio. We conclude that the Myr:DHA ratio represents a better biomarker of NAFLD than the n-6 PUFA:n-3 PUFA ratio. Future studies are necessary for verifying this observation.
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Affiliation(s)
- Marina Masetto Antunes
- Post-Graduation Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Brazil
| | - Guilherme Godoy
- Post-Graduation Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Brazil
| | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil
| | | | - Roberto Barbosa Bazotte
- Post-Graduation Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Brazil.,Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil
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Szabó J, Maróti G, Solymosi N, Andrásofszky E, Tuboly T, Bersényi A, Bruckner G, Hullár I. Fructose, glucose and fat interrelationships with metabolic pathway regulation and effects on the gut microbiota. Acta Vet Hung 2021; 69:134-156. [PMID: 34224398 DOI: 10.1556/004.2021.00022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 06/04/2021] [Indexed: 12/14/2022]
Abstract
The purpose of this 30-day feeding study was to elucidate the changes, correlations, and mechanisms caused by the replacement of the starch content of the AIN-93G diet (St) with glucose (G), fructose (F) or lard (L) in body and organ weights, metabolic changes and caecal microbiota composition in rats (Wistar, SPF). The body weight gain of rats on the F diet was 12% less (P = 0.12) than in the St group. Rats on the L diet consumed 18.6% less feed, 31% more energy and gained 58.4% more than the animals on the St diet, indicating that, in addition to higher energy intake, better feed utilisation is a key factor in the obesogenic effect of diets of high nutrient and energy density. The G, F and L diets significantly increased the lipid content of the liver (St: 7.01 ± 1.48; G: 14.53 ± 8.77; F: 16.73 ± 8.77; L: 19.86 ± 4.92% of DM), suggesting that lipid accumulation in the liver is not a fructose-specific process. Relative to the St control, specific glucose effects were the decreasing serum glucagon (-41%) concentrations and glucagon/leptin ratio and the increasing serum leptin concentrations (+26%); specific fructose effects were the increased weights of the kidney, spleen, epididymal fat and the decreased weight of retroperitoneal fat and the lower immune response, as well as the increased insulin (+26%), glucagon (+26%) and decreased leptin (-25%) levels. This suggests a mild insulin resistance and catabolic metabolism in F rats. Specific lard effects were the decreased insulin (-9.14%) and increased glucagon (+40.44%) and leptin (+44.92%) levels. Relative to St, all diets increased the operational taxonomic units of the phylum Bacteroidetes. G and L decreased, while F increased the proportion of Firmicutes. F and L diets decreased the proportions of Actinobacteria, Proteobacteria and Verrucomicrobia. Correlation and centrality analyses were conducted to ascertain the positive and negative correlations and relative weights of the 32 parameters studied in the metabolic network. These correlations and the underlying potential mechanisms are discussed.
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Affiliation(s)
- József Szabó
- 1Department of Animal Breeding, Nutrition and Laboratory Animal Science, University of Veterinary Medicine, P. O. Box 2, H-1400 Budapest, Hungary
| | - Gergely Maróti
- 2Biological Research Centre, Institute of Plant Biology, Szeged, Hungary
| | - Norbert Solymosi
- 3Centre for Bioinformatics, University of Veterinary Medicine, Budapest, Hungary
| | - Emese Andrásofszky
- 1Department of Animal Breeding, Nutrition and Laboratory Animal Science, University of Veterinary Medicine, P. O. Box 2, H-1400 Budapest, Hungary
| | - Tamás Tuboly
- 4Department of Microbiology and Infectious Diseases, University of Veterinary Medicine, Budapest, Hungary
| | - András Bersényi
- 1Department of Animal Breeding, Nutrition and Laboratory Animal Science, University of Veterinary Medicine, P. O. Box 2, H-1400 Budapest, Hungary
| | - Geza Bruckner
- 5Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, USA
| | - István Hullár
- 1Department of Animal Breeding, Nutrition and Laboratory Animal Science, University of Veterinary Medicine, P. O. Box 2, H-1400 Budapest, Hungary
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Chen CY, Li Y, Zeng N, He L, Zhang X, Tu T, Tang Q, Alba M, Mir S, Stiles EX, Hong H, Cadenas E, Stolz AA, Li G, Stiles BL. Inhibition of Estrogen-Related Receptor α Blocks Liver Steatosis and Steatohepatitis and Attenuates Triglyceride Biosynthesis. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1240-1254. [PMID: 33894178 PMCID: PMC8261472 DOI: 10.1016/j.ajpath.2021.04.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 03/08/2021] [Accepted: 04/12/2021] [Indexed: 01/02/2023]
Abstract
The estrogen-related receptor (ERR) family of orphan nuclear receptors are transcriptional activators for genes involved in mitochondrial bioenergetics and metabolism. The goal of this study was to explore the role of ERRα in lipid metabolism and the potential effect of inhibiting ERRα on the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In the current study, three experimental mouse models: high-fat diet, high-carbohydrate diet, and a genetic model of hepatic insulin resistance where the liver hyperinsulinemia signal is mimicked via hepatic deletion of Pten (phosphatase and tensin homolog deleted on chromosome 10), the negative regulator of the insulin/phosphatidylinositol 3-kinase signaling pathway, were used. A recently developed small-molecule inhibitor for ERRα was used to demonstrate that inhibiting ERRα blocked NAFLD development induced by either high-carbohydrate diet or high-fat diet feeding. ERRα inhibition also diminished lipid accumulation and attenuated NASH development in the Pten null mice. Glycerolipid synthesis was discovered as an additional mechanism for ERRα-regulated NAFLD/NASH development and glycerophosphate acyltransferase 4 was identified as a novel transcriptional target of ERRα. In summary, these results establish ERRα as a major transcriptional regulator of lipid biosynthesis in addition to its characterized primary function as a regulator for mitochondrial function. This study recognizes ERRα as a potential target for NAFLD/NASH treatment and elucidates novel signaling pathways regulated by ERRα.
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Affiliation(s)
- Chien-Yu Chen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Yang Li
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Ni Zeng
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Lina He
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Xinwen Zhang
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Taojian Tu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Qi Tang
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Mario Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Sabrina Mir
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Eileen X Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Handan Hong
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Enrique Cadenas
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California; Department of Biochemistry, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Andrew A Stolz
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Gang Li
- Faculty of Health Sciences, University of Macau, Macau
| | - Bangyan L Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.
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Dankel SN, Bjørndal B, Lindquist C, Grinna ML, Rossmann CR, Bohov P, Nygård O, Hallström S, Strand E, Berge RK. Hepatic Energy Metabolism Underlying Differential Lipidomic Responses to High-Carbohydrate and High-Fat Diets in Male Wistar Rats. J Nutr 2021; 151:2610-2621. [PMID: 34132338 PMCID: PMC8417924 DOI: 10.1093/jn/nxab178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/17/2021] [Accepted: 05/11/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Low-carbohydrate diets are suggested to exert metabolic benefits by reducing circulating triacylglycerol (TG) concentrations, possibly by enhancing mitochondrial activity. OBJECTIVE We aimed to elucidate mechanisms by which dietary carbohydrate and fat differentially affect hepatic and circulating TG, and how these mechanisms relate to fatty acid composition. METHODS Six-week-old, ∼300 g male Wistar rats were fed a high-carbohydrate, low-fat [HC; 61.3% of energy (E%) carbohydrate] or a low-carbohydrate, high-fat (HF; 63.5 E% fat) diet for 4 wk. Parameters of lipid metabolism and mitochondrial function were measured in plasma and liver, with fatty acid composition (GC), high-energy phosphates (HPLC), carnitine metabolites (HPLC-MS/MS), and hepatic gene expression (qPCR) as main outcomes. RESULTS In HC-fed rats, plasma TG was double and hepatic TG 27% of that in HF-fed rats. The proportion of oleic acid (18:1n-9) was 60% higher after HF vs. HC feeding while the proportion of palmitoleic acid (16:1n-7) and vaccenic acid (18:1n-7), and estimated activities of stearoyl-CoA desaturase, SCD-16 (16:1n-7/16:0), and de novo lipogenesis (16:0/18:2n-6) were 1.5-7.5-fold in HC vs. HF-fed rats. Accordingly, hepatic expression of fatty acid synthase (Fasn) and acetyl-CoA carboxylase (Acaca/Acc) was strongly upregulated after HC feeding, accompanied with 8-fold higher FAS activity and doubled ACC activity. There were no differences in expression of liver-specific biomarkers of mitochondrial biogenesis and activity (Cytc, Tfam, Cpt1, Cpt2, Ucp2, Hmgcs2); concentrations of ATP, AMP, and energy charge; plasma carnitine/acylcarnitine metabolites; or peroxisomal fatty acid oxidation. CONCLUSIONS In male Wistar rats, dietary carbohydrate was converted into specific fatty acids via hepatic lipogenesis, contributing to higher plasma TG and total fatty acids compared with high-fat feeding. In contrast, the high-fat, low-carbohydrate feeding increased hepatic fatty acid content, without affecting hepatic mitochondrial fatty acid oxidation.
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Affiliation(s)
| | - Bodil Bjørndal
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Carine Lindquist
- Department of Clinical Science, University of Bergen, Bergen, Norway,Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Mari L Grinna
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | | | - Pavol Bohov
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Ottar Nygård
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway,Department of Clinical Science, University of Bergen, Bergen, Norway,Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Seth Hallström
- Division of Physiological Chemistry, Medical University of Graz, Graz, Austria
| | - Elin Strand
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
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Gerstner C, Saín J, Lavandera J, González M, Bernal C. Functional milk fat enriched in conjugated linoleic acid prevented liver lipid accumulation induced by a high-fat diet in male rats. Food Funct 2021; 12:5051-5065. [PMID: 33960342 DOI: 10.1039/d0fo03296d] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The aim was to investigate the potential effect of functional milk fat (FMF), naturally enriched in conjugated linoleic acid, on the prevention of liver lipid accumulation and some biochemical mechanisms involved in the liver triacylglycerol (TAG) regulation in high-fat (HF) fed rats. Male Wistar rats were fed (60 days) with S7 (soybean oil, 7%) or HF diets: S30 (soybean oil, 30%), MF30 (soybean oil, 3% + milk fat -MF-, 27%) or FMF30 (soybean oil, 3% + FMF, 27%). Nutritional parameters, hepatic fatty acid (FA) composition, liver and serum TAG levels, hepatic TAG secretion rate (TAG-SR), lipoprotein lipase (LPL) activity in adipose tissue and muscle, activities and/or mRNA levels of lipogenic and β-oxidative enzymes, and mRNA levels of transcription factors and FA transport proteins were assessed. The hepatic lipid accumulation induced by the S30 diet was associated with increased mRNA levels of FA transporters; and it was prevented by FMF through an increase in the hepatic TAG-SR, carnitine palmitoyltransferase-1a activity and peroxisome proliferator-activated receptor alpha mRNA levels, as well as by a reduction of the mRNA levels of FA transporters. The hypotriacylglyceridaemia observed in S30 was related with an increased LPL activity in adipose tissue and it was reverted by FMF through the increased hepatic TAG-SR. In brief, FMF prevented the liver lipid accumulation induced by HF diets by increasing the hepatic TAG-SR and β-oxidation, and reducing the hepatic FA uptake. The increased hepatic TAG-SR induced by FMF could be responsible for the attenuation of serum TAG alterations.
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Affiliation(s)
- Carolina Gerstner
- Cátedra de Bromatología y Nutrición, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina.
| | - Juliana Saín
- Cátedra de Bromatología y Nutrición, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina. and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
| | - Jimena Lavandera
- Cátedra de Bromatología y Nutrición, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina. and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
| | - Marcela González
- Cátedra de Bromatología y Nutrición, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina.
| | - Claudio Bernal
- Cátedra de Bromatología y Nutrición, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina. and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
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Theodoro JMV, Martinez ODM, Grancieri M, Toledo RCL, Dias Martins AM, Dias DM, Carvalho CWP, Martino HSD. Germinated millet flour (Pennisetum glaucum (L.) R. Br.) reduces inflammation, oxidative stress, and liver steatosis in rats fed with high-fat high-fructose diet. J Cereal Sci 2021. [DOI: 10.1016/j.jcs.2021.103207] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Dry heated whole sorghum flour (BRS 305) with high tannin and resistant starch improves glucose metabolism, modulates adiposity, and reduces liver steatosis and lipogenesis in Wistar rats fed with a high-fat high-fructose diet. J Cereal Sci 2021. [DOI: 10.1016/j.jcs.2021.103201] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Protective effects of whey protein concentrate admixtured of curcumin on metabolic control, inflammation and oxidative stress in Wistar rats submitted to exhaustive exercise. Br J Nutr 2021; 127:526-539. [PMID: 33902765 DOI: 10.1017/s0007114521001355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This work aimed to evaluate the effects of whey protein concentrate (WPC) admixtured of curcumin on metabolic control, inflammation and oxidative stress in Wistar rats submitted to exhaustive exercise. A total of forty-eight male rats were divided into six experimental groups (n 8): standard diet group (AIN-93M), standard diet submitted to exhaustion test group (AIN-93M ET), WPC admixtured of curcumin group (WPC + CCM), WPC + CCM submitted to exhaustion test group (WPC + CCM ET), CCM group and CCM subjected to exhaustion test group (CCM ET). The swimming exhaustion test was performed after 4 weeks of experiment. The consumption of WPC + CCM as well as isolated CCM did not alter the biometric measurements, the animals' food consumption and the hepatic and kidney function, as well as the protein balance of the animals (P > 0·05), but reduced the glycaemia and the gene expression of TNF-α and IL-6 and increased the expression of IL-10 (P < 0·05). The animals that were submitted to the exhaustion test (AIN-93M ET) showed higher aspartate aminotransferase values when compared to the animals that did not perform the exercise (AIN-93 M) (P < 0·05). WPC + CCM reduced the concentration of nitric oxide, carbonylated protein and increased the concentration of catalase (P < 0·05). Both (WPC + CCM and CCM) were able to increase the concentrations of superoxide dismutase (P < 0·05). We concluded that the WPC admixtured of CCM represents a strategy capable of decreasing blood glucose and oxidative and inflammatory damage caused by exhaustive physical exercise in swimming.
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Antunes MM, Godoy G, Fernandes IDL, Manin LP, Zappielo C, Masi LN, de Oliveira VAB, Visentainer JV, Curi R, Bazotte RB. The Dietary Replacement of Soybean Oil by Canola Oil Does Not Prevent Liver Fatty Acid Accumulation and Liver Inflammation in Mice. Nutrients 2020; 12:E3667. [PMID: 33260679 PMCID: PMC7760057 DOI: 10.3390/nu12123667] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/16/2020] [Accepted: 11/22/2020] [Indexed: 12/24/2022] Open
Abstract
A high-carbohydrate diet (HCD) is a well-established experimental model of accelerated liver fatty acid (FA) deposition and inflammation. In this study, we evaluated whether canola oil can prevent these physiopathological changes. We evaluated hepatic FA accumulation and inflammation in mice fed with a HCD (72.1% carbohydrates) and either canola oil (C group) or soybean oil (S group) as a lipid source for 0, 7, 14, 28, or 56 days. Liver FA compositions were analyzed by gas chromatography. The mRNA expression of acetyl-CoA carboxylase 1 (ACC1) was measured as an indicator of lipogenesis. The mRNA expression of F4/80, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-10, as mediators of liver inflammation, were also measured. The C group stored less n-6 polyunsaturated FAs (n-6 PUFAs) and had more intense lipid deposition of monounsaturated FAs (MUFAs), n-3 PUFAs, and total FAs. The C group also showed higher ACC1 expression. Moreover, on day 56, the C group showed higher expressions of the inflammatory genes F4/80, TNF-α, IL-1β, and IL-6, as well as the anti-inflammatory IL-10. In conclusion, a diet containing canola oil as a lipid source does not prevent the fatty acid accumulation and inflammation induced by a HCD.
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Affiliation(s)
- Marina Masetto Antunes
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá 87020-900, Brazil; (M.M.A.); (G.G.)
| | - Guilherme Godoy
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá 87020-900, Brazil; (M.M.A.); (G.G.)
| | - Ingrid de Lima Fernandes
- Department of Chemistry, State University of Maringá, Maringá 87020-900, Brazil; (I.d.L.F.); (L.P.M.); (C.Z.); (J.V.V.)
| | - Luciana Pelissari Manin
- Department of Chemistry, State University of Maringá, Maringá 87020-900, Brazil; (I.d.L.F.); (L.P.M.); (C.Z.); (J.V.V.)
| | - Caroline Zappielo
- Department of Chemistry, State University of Maringá, Maringá 87020-900, Brazil; (I.d.L.F.); (L.P.M.); (C.Z.); (J.V.V.)
| | - Laureane Nunes Masi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 03342-000, Brazil; (L.N.M.); (V.A.B.d.O.); (R.C.)
| | - Vivian Araújo Barbosa de Oliveira
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 03342-000, Brazil; (L.N.M.); (V.A.B.d.O.); (R.C.)
| | - Jesuí Vergílio Visentainer
- Department of Chemistry, State University of Maringá, Maringá 87020-900, Brazil; (I.d.L.F.); (L.P.M.); (C.Z.); (J.V.V.)
| | - Rui Curi
- Interdisciplinary Post-Graduate Program in Health Sciences, Cruzeiro do Sul University, São Paulo 03342-000, Brazil; (L.N.M.); (V.A.B.d.O.); (R.C.)
| | - Roberto Barbosa Bazotte
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá 87020-900, Brazil; (M.M.A.); (G.G.)
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Benlebna M, Balas L, Bonafos B, Pessemesse L, Fouret G, Vigor C, Gaillet S, Grober J, Bernex F, Landrier JF, Kuda O, Durand T, Coudray C, Casas F, Feillet-Coudray C. Long-term intake of 9-PAHPA or 9-OAHPA modulates favorably the basal metabolism and exerts an insulin sensitizing effect in obesogenic diet-fed mice. Eur J Nutr 2020; 60:2013-2027. [PMID: 32989473 DOI: 10.1007/s00394-020-02391-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Fatty acid esters of hydroxy fatty acids (FAHFAs) are a large family of endogenous bioactive lipids. To date, most of the studied FAHFAs are branched regioisomers of Palmitic Acid Hydroxyl Stearic Acid (PAHSA) that were reported to possess anti-diabetic and anti-inflammatory activity in humans and rodents. Recently, we have demonstrated that 9-PAHPA or 9-OAHPA intake increased basal metabolism and enhanced insulin sensitivity in healthy control diet-fed mice but induced liver damage in some mice. The present work aims to explore whether a long-term intake of 9-PAHPA or 9-OAHPA may have similar effects in obesogenic diet-fed mice. METHODS C57Bl6 mice were fed with a control or high fat-high sugar (HFHS) diets for 12 weeks. The HFHS diet was supplemented or not with 9-PAHPA or 9-OAHPA. Whole-body metabolism was explored. Glucose and lipid metabolism as well as mitochondrial activity and oxidative stress status were analyzed. RESULTS As expected, the intake of HFHS diet led to obesity and lower insulin sensitivity with minor effects on liver parameters. The long-term intake of 9-PAHPA or 9-OAHPA modulated favorably the basal metabolism and improved insulin sensitivity as measured by insulin tolerance test. On the contrary to what we have reported previously in healthy mice, no marked effect for these FAHFAs was observed on liver metabolism of obese diabetic mice. CONCLUSION This study indicates that both 9-PAHPA and 9-OAHPA may have interesting insulin-sensitizing effects in obese mice with lower insulin sensitivity.
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Affiliation(s)
| | - Laurence Balas
- Institut Des Biomolécules Max Mousseron (IBMM), Université de Montpellier, CNRS, ENSCM, Montpellier, France
| | | | | | | | - Claire Vigor
- Institut Des Biomolécules Max Mousseron (IBMM), Université de Montpellier, CNRS, ENSCM, Montpellier, France
| | | | - Jacques Grober
- LNC UMR1231, INSERM, Univ Bourgogne Franche-Comté, Agrosup Dijon, LipSTIC LabEx, Dijon, France
| | - Florence Bernex
- INSERM, U1194, Network of Experimental Histology, BioCampus, CNRS, UMS3426, Montpellier, France
| | | | - Ondrej Kuda
- Department of Metabolism of Bioactive Lipids, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic
| | - Thierry Durand
- Institut Des Biomolécules Max Mousseron (IBMM), Université de Montpellier, CNRS, ENSCM, Montpellier, France
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Draycott SAV, Elmes MJ, Muhlhausler BS, Langley-Evans S. Omega-6:Omega-3 Fatty Acid Ratio and Total Fat Content of the Maternal Diet Alter Offspring Growth and Fat Deposition in the Rat. Nutrients 2020; 12:nu12092505. [PMID: 32825093 PMCID: PMC7551768 DOI: 10.3390/nu12092505] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/06/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022] Open
Abstract
Omega-3 long-chain polyunsaturated fatty acids (LCPUFA) have been shown to inhibit lipogenesis and adipogenesis in adult rats. Their possible early life effects on offspring fat deposition, however, remain to be established. To investigate this, female Wistar rats (n = 6–9 per group) were fed either a 9:1 ratio of linoleic acid (LA) to alpha-linolenic acid (ALA) or a lower 1:1.5 ratio during pregnancy and lactation. Each ratio was fed at two total fat levels (18% vs. 36% fat w/w) and offspring were weaned onto standard laboratory chow. Offspring exposed to a 36% fat diet, irrespective of maternal dietary LA:ALA ratio, were lighter (male, 27 g lighter; female 19 g lighter; p < 0.0001) than those exposed to an 18% fat diet between 3 and 8 weeks of age. Offspring exposed to a low LA (18% fat) diet had higher proportions of circulating omega-3 LCPUFA and increased gonadal fat mass at 4 weeks of age (p < 0.05). Reduced Srebf1 mRNA expression of hepatic (p < 0.01), gonadal fat (p < 0.05) and retroperitoneal fat (p < 0.05) tissue was observed at 4 weeks of age in male and female offspring exposed to a 36% fat diet, and hepatic Srebf1 mRNA was also reduced in male offspring at 8 weeks of age (p < 0.05). Thus, while offspring fat deposition appeared to be sensitive to both maternal dietary LA:ALA ratio and total fat content, offspring growth and lipogenic capacity of tissues appeared to be more sensitive to maternal dietary fat content.
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Affiliation(s)
- Sally A. V. Draycott
- Sutton Bonington Campus, School of Biosciences, University of Nottingham, Loughborough LE12 5RD, UK; (M.J.E.); (S.L.-E.)
- Food and Nutrition Research Group, Department of Food and Wine Science, School of Agriculture, Food and Wine, University of Adelaide, Adelaide, SA 5064, Australia;
- Correspondence:
| | - Matthew J. Elmes
- Sutton Bonington Campus, School of Biosciences, University of Nottingham, Loughborough LE12 5RD, UK; (M.J.E.); (S.L.-E.)
| | - Beverly S. Muhlhausler
- Food and Nutrition Research Group, Department of Food and Wine Science, School of Agriculture, Food and Wine, University of Adelaide, Adelaide, SA 5064, Australia;
- Commonwealth Scientific and Industrial Research Organisation, Adelaide, SA 5000, Australia
| | - Simon Langley-Evans
- Sutton Bonington Campus, School of Biosciences, University of Nottingham, Loughborough LE12 5RD, UK; (M.J.E.); (S.L.-E.)
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13
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Determining the contribution of a high-fructose corn syrup formulation to hepatic glycogen synthesis during ad-libitum feeding in mice. Sci Rep 2020; 10:12852. [PMID: 32733017 PMCID: PMC7393509 DOI: 10.1038/s41598-020-69820-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 07/06/2020] [Indexed: 11/28/2022] Open
Abstract
Excessive sugar intake including high-fructose corn syrup (HFCS) is implicated in the rise of obesity, insulin resistance and non-alcoholic fatty liver disease. Liver glycogen synthesis is influenced by both fructose and insulin signaling. Therefore, the effect of HFCS on hepatic glycogenesis was evaluated in mice feeding ad-libitum. Using deuterated water: the fraction of glycogen derived from triose-P sources, Krebs cycle substrates, and direct pathway + cycling, was measured in 9 normal-chow fed mice (NC) and 12 mice fed normal chow plus a 55% fructose/45% glucose mix in the drinking water at 30% w/v (HFCS-55). This was enriched with [U-13C]fructose or [U-13C]glucose to determine the contribution of each to glycogenesis. For NC, direct pathway + cycling, Krebs cycle, and triose-P sources accounted for 66 ± 0.7%, 23 ± 0.8% and 11 ± 0.4% of glycogen synthesis, respectively. HFCS-55 mice had similar direct pathway + cycling (64 ± 1%) but lower Krebs cycle (12 ± 1%, p < 0.001) and higher triose-P contributions (24 ± 1%, p < 0.001). HFCS-55-fructose contributed 17 ± 1% via triose-P and 2 ± 0% via Krebs cycle. HFCS-55-glucose contributed 16 ± 3% via direct pathway and 1 ± 0% via Krebs cycle. In conclusion, HFCS-55 supplementation resulted in similar hepatic glycogen deposition rates. Indirect pathway contributions shifted from Krebs cycle to Triose-P sources reflecting HFCS-55-fructose utilization, while HFCS-55-glucose was incorporated almost exclusively by the direct pathway.
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14
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Martin GG, Landrock D, McIntosh AL, Milligan S, Landrock KK, Kier AB, Mackie J, Schroeder F. High Glucose and Liver Fatty Acid Binding Protein Gene Ablation Differentially Impact Whole Body and Liver Phenotype in High-Fat Pair-Fed Mice. Lipids 2020; 55:309-327. [PMID: 32314395 DOI: 10.1002/lipd.12238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 03/12/2020] [Accepted: 03/30/2020] [Indexed: 12/14/2022]
Abstract
Ad libitum-fed diets high in fat and carbohydrate (especially fructose) induce weight gain, obesity, and nonalcoholic fatty liver disease (NAFLD) in humans and animal models. However, interpretation is complicated since ad libitum feeding of such diets induces hyperphagia and upregulates expression of liver fatty acid binding protein (L-FABP)-a protein intimately involved in fatty acid and glucose regulation of lipid metabolism. Wild-type (WT) and L-fabp gene ablated (LKO) mice were pair-fed either high-fat diet (HFD) or high-fat/high-glucose diet (HFGD) wherein total carbohydrate was maintained constant but the proportion of glucose was increased at the expense of fructose. In LKO mice, the pair-fed HFD increased body weight and lean tissue mass (LTM) but had no effect on fat tissue mass (FTM) or hepatic fatty vacuolation as compared to pair-fed WT counterparts. These LKO mice exhibited upregulation of hepatic proteins in fatty acid uptake and cytosolic transport (caveolin and sterol carrier protein-2), but lower hepatic fatty acid oxidation (decreased serum β-hydroxybutyrate). LKO mice pair-fed HFGD also exhibited increased body weight; however, these mice had increased FTM, not LTM, and increased hepatic fatty vacuolation as compared to pair-fed WT counterparts. These LKO mice also exhibited upregulation of hepatic proteins in fatty acid uptake and cytosolic transport (caveolin and acyl-CoA binding protein, but not sterol carrier protein-2), but there was no change in hepatic fatty acid oxidation (serum β-hydroxybutyrate) as compared to pair-fed WT counterparts.
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Affiliation(s)
- Gregory G Martin
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843, USA
| | - Danilo Landrock
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843, USA
| | - Avery L McIntosh
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843, USA
| | - Sherrelle Milligan
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843, USA
| | - Kerstin K Landrock
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843, USA
| | - Ann B Kier
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843, USA
| | - John Mackie
- Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843, USA
| | - Friedhelm Schroeder
- Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843, USA
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15
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Ahmed O, Pramfalk C, Pedrelli M, Olin M, Steffensen KR, Eriksson M, Parini P. Genetic depletion of Soat2 diminishes hepatic steatosis via genes regulating de novo lipogenesis and by GLUT2 protein in female mice. Dig Liver Dis 2019; 51:1016-1022. [PMID: 30630736 DOI: 10.1016/j.dld.2018.12.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 11/23/2018] [Accepted: 12/10/2018] [Indexed: 12/11/2022]
Abstract
Depletion of the cholesterol esterifying enzyme acyl-Coenzyme A: cholesterol acyltransferase 2 (ACAT2, encoded by Soat2) protects mice from atherosclerosis, diet-induced hypercholesterolemia, and hepatic steatosis when fed high-cholesterol diet. The glucose transporter 2 (GLUT2) represents the main gate of glucose uptake by the liver. Lipid synthesis from glucose (de novo lipogenesis; DNL) plays a pivotal role in the development of hepatic steatosis. Inhibition of DNL is a successful approach to reverse hepatic steatosis, as shown by different studies in mice and humans. Here we aimed to investigate whether depletion of Soat2 per se can reduce hepatic steatosis, also in the presence of very low levels of cholesterol in the diet, and the underlying mechanisms. Female Soat2-/- and wild type mice were either fed high-fat or high-carbohydrate diet and both contained <0.05% (w/w) cholesterol. Analysis in serum, liver, muscles and adipose tissues were performed. We found Soat2-/- mice fed high-fat, low-cholesterol diet to have less hepatic steatosis, decreased expression of genes involved in DNL and lower hepatic GLUT2. Similar findings were found in Soat2-/- mice fed high-carbohydrate, low-cholesterol diet. CONCLUSION: Depletion of Soat2 reduces hepatic steatosis independently of the presence of high levels of cholesterol in the diet. Our study provides a link between hepatic cholesterol esterification, DNL, and GLUT2.
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Affiliation(s)
- O Ahmed
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Biochemistry, Faculty of Medicine, Khartoum University, Khartoum, Sudan
| | - C Pramfalk
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - M Pedrelli
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - M Olin
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - K R Steffensen
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - M Eriksson
- Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Patient Area Nephrology and Endocrinology, Inflammation and Infection Theme, Karolinska University Hospital, Stockholm, Sweden
| | - P Parini
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Metabolism Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Patient Area Nephrology and Endocrinology, Inflammation and Infection Theme, Karolinska University Hospital, Stockholm, Sweden.
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16
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Lian J, Watts R, Quiroga AD, Beggs MR, Alexander RT, Lehner R. Ces1d deficiency protects against high-sucrose diet-induced hepatic triacylglycerol accumulation. J Lipid Res 2019; 60:880-891. [PMID: 30737251 PMCID: PMC6446703 DOI: 10.1194/jlr.m092544] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Indexed: 12/20/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Triacylglycerol accumulation in the liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis (DNL) in humans contributes to fat accumulation in the liver and to NAFLD progression. Mice deficient in carboxylesterase (Ces)1d expression are protected from high-fat diet-induced hepatic steatosis. To investigate whether loss of Ces1d can also mitigate steatosis induced by over-activated DNL, WT and Ces1d-deficient mice were fed a lipogenic high-sucrose diet (HSD). We found that Ces1d-deficient mice were protected from HSD-induced hepatic lipid accumulation. Mechanistically, Ces1d deficiency leads to activation of AMP-activated protein kinase and inhibitory phosphorylation of acetyl-CoA carboxylase. Together with our previous demonstration that Ces1d deficiency attenuated high-fat diet-induced steatosis, this study suggests that inhibition of CES1 (the human ortholog of Ces1d) might represent a novel pharmacological target for prevention and treatment of NAFLD.
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Affiliation(s)
- Jihong Lian
- Group on Molecular and Cell Biology of Lipids University of Alberta, Alberta, Canada; Departments of Pediatrics, University of Alberta, Alberta, Canada
| | - Russell Watts
- Group on Molecular and Cell Biology of Lipids University of Alberta, Alberta, Canada; Departments of Pediatrics, University of Alberta, Alberta, Canada
| | - Ariel D Quiroga
- Instituto de Fisiología Experimental (IFISE), Área Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Rosario, Argentina
| | | | - R Todd Alexander
- Departments of Pediatrics, University of Alberta, Alberta, Canada; Physiology, University of Alberta, Alberta, Canada
| | - Richard Lehner
- Group on Molecular and Cell Biology of Lipids University of Alberta, Alberta, Canada; Departments of Pediatrics, University of Alberta, Alberta, Canada; Cell Biology, University of Alberta, Alberta, Canada.
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17
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Effects of Diet-Induced Obesity and Deficient in Vitamin D on Spermatozoa Function and DNA Integrity in Sprague-Dawley Rats. BIOMED RESEARCH INTERNATIONAL 2018; 2018:5479057. [PMID: 30596095 PMCID: PMC6286761 DOI: 10.1155/2018/5479057] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 10/17/2018] [Accepted: 11/12/2018] [Indexed: 12/28/2022]
Abstract
Obesity has adverse effects on male fertility and usually is diagnosed with a prevalence of vitamin D deficiency (VD−). Discussion on the impact of obesity/VD− on sperm function has been limited. This study analyzed the effects of diet-induced obesity/VD− on viability and plasma membrane integrity (PMI), superoxide anion (O2−) level, and DNA fragmentation (DNAfrag) in sperm Sprague-Dawley rats. The males were randomized into four groups and fed for a period of 12 weeks: G1: control diet with vitamin D (C/VD+), G2: control diet without vitamin D (C/VD−), G3: high-fat diet with vitamin D (HF/VD+), and G4: high-fat diet without vitamin D (HF/VD−). Sperm function parameters were analyzed by flow cytometry. PMI percentages and O2− levels were not affected by any of the diets. DNA fragmentation was increasing significantly (p<0.05) in the spermatozoa of animals with diets vitamin D deficient (G2) and diet-induced obesity (G4). Our results allow us to point out that diet-induced obesity and VD− produce greater damage in DNA sperm of rats. The use of nutraceuticals containing vitamin D could be reducing the risk of fragmentation of DNA in spermatozoa.
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18
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Zeng Y, David J, Rémond D, Dardevet D, Savary-Auzeloux I, Polakof S. Peripheral Blood Mononuclear Cell Metabolism Acutely Adapted to Postprandial Transition and Mainly Reflected Metabolic Adipose Tissue Adaptations to a High-Fat Diet in Minipigs. Nutrients 2018; 10:nu10111816. [PMID: 30469379 PMCID: PMC6267178 DOI: 10.3390/nu10111816] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 10/26/2018] [Accepted: 11/15/2018] [Indexed: 11/16/2022] Open
Abstract
Although peripheral blood mononuclear cells (PBMCs) are widely used as a valuable tool able to provide biomarkers of health and diseases, little is known about PBMC functional (biochemistry-based) metabolism, particularly following short-term nutritional challenges. In the present study, the metabolic capacity of minipig PBMCs to respond to nutritional challenges was explored at the biochemical and molecular levels. The changes observed in enzyme activities following a control test meal revealed that PBMC metabolism is highly reactive to the arrival of nutrients and hormones in the circulation. The consumption, for the first time, of a high fat⁻high sucrose (HFHS) meal delayed or sharply reduced most of the observed postprandial metabolic features. In a second experiment, minipigs were subjected to two-month HFHS feeding. The time-course follow-up of metabolic changes in PBMCs showed that most of the adaptations to the new diet took place during the first week. By comparing metabolic (biochemical and molecular) PMBC profiles to those of the liver, skeletal muscle, and adipose tissue, we concluded that although PBMCs conserved common features with all of them, their response to the HFHS diet was closely related to that of the adipose tissue. As a whole, our results show that PBMC metabolism, particularly during short-term (postprandial) challenges, could be used to evaluate the whole-body metabolic status of an individual. This could be particularly interesting for early diagnosis of metabolic disease installation, when fasting clinical analyses fail to diagnose the path towards the pathology.
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Affiliation(s)
- Yuchun Zeng
- INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
| | - Jérémie David
- INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
| | - Didier Rémond
- INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
| | - Dominique Dardevet
- INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
| | - Isabelle Savary-Auzeloux
- INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
| | - Sergio Polakof
- INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France.
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19
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Worsch S, Heikenwalder M, Hauner H, Bader BL. Dietary n-3 long-chain polyunsaturated fatty acids upregulate energy dissipating metabolic pathways conveying anti-obesogenic effects in mice. Nutr Metab (Lond) 2018; 15:65. [PMID: 30275870 PMCID: PMC6158869 DOI: 10.1186/s12986-018-0291-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 07/20/2018] [Indexed: 12/18/2022] Open
Abstract
Background We previously reported on the anti-obesogenic and anti-inflammatory effects associated with n-3 long-chain polyunsaturated fatty acids (LCPUFA) in our diet-induced obesity (DIO) mouse model. Two isocaloric high-fat diets (HFDs; 48 kJ% fat), HFD (HF) and n-3 LCPUFA-enriched HFD (HF/n-3), and a control diet (C; 13 kJ% fat) were used. The underlying mechanisms however have largely remained unclear. Here, we assessed whether the reduced fat mass reflected n-3 LCPUFA-induced expression changes in lipid metabolism of the intestine, liver, and interscapular brown adipose tissue (iBAT), as well as increased iBAT thermogenic capacity. Methods For HF/n-3, saturated and monounsaturated fatty acids were partially substituted by n-3 LCPUFA eicosapentaenoic acid and docosahexaenoic acid to achieve a balanced n-6/n-3 PUFA ratio (0.84) compared to the unbalanced ratios of HF (13.5) and C (9.85). Intestine, liver and iBAT from male C57BL/6 J mice, fed defined soybean/palm oil-based diets for 12 weeks, were further analysed. Gene and protein expression analyses, immunohistochemistry and correlation analyses for metabolic interactions were performed. Results Compared to HF and C, our analyses suggest significantly diminished de novo lipogenesis (DNL) and/or increased hepatic and intestinal fatty acid oxidation (ω-oxidation and peroxisomal β-oxidation) in HF/n-3 mice. For iBAT, the thermogenic potential was enhanced upon HF/n-3 consistent with upregulated expression for uncoupling protein-1 and genes involved in mitochondrial biogenesis. In addition, a higher capacity for the supply and oxidation of fatty acids was observed and expression and correlation analyses indicated a coordinated regulation of energy metabolism and futile cycling of triacylglycerol (TAG). Moreover, HF/n-3 significantly increased the number of anti-inflammatory macrophages and eosinophils and significantly enhanced the levels of activated AMP-activated protein kinase α (AMPKα), peroxisome proliferator-activated receptor α (PPARα) and fibroblast growth factor 21 (FGF21). Conclusions Our data suggest that by targeting transcriptional regulatory pathways, AMPKα, and FGF21 as potential mediators, HF/n-3 activated less efficient pathways for energy production, such as peroxisomal β-oxidation, increased ATP consumption upon the induction of futile cycling of TAG, and additionally increased the thermogenic and oxidative potential of iBAT. Therefore, we consider n-3 LCPUFA as the potent inducer for upregulating energy dissipating metabolic pathways conveying anti-obesogenic effects in mice. Electronic supplementary material The online version of this article (10.1186/s12986-018-0291-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Stefanie Worsch
- 1Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technical University of Munich, Freising, Germany.,2ZIEL - Institute for Food and Health, Nutritional Medicine Unit, Technical University of Munich, Freising, Germany
| | - Mathias Heikenwalder
- 4Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hans Hauner
- 1Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technical University of Munich, Freising, Germany.,2ZIEL - Institute for Food and Health, Nutritional Medicine Unit, Technical University of Munich, Freising, Germany.,Else Kroener-Fresenius-Center for Nutritional Medicine, University Hospital Klinikum rechts der Isar, Uptown München-Campus D, Technical University of Munich, Georg-Brauchle-Ring 60/62, 80992 Munich, Germany
| | - Bernhard L Bader
- 1Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technical University of Munich, Freising, Germany.,2ZIEL - Institute for Food and Health, Nutritional Medicine Unit, Technical University of Munich, Freising, Germany.,Else Kroener-Fresenius-Center for Nutritional Medicine, University Hospital Klinikum rechts der Isar, Uptown München-Campus D, Technical University of Munich, Georg-Brauchle-Ring 60/62, 80992 Munich, Germany
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20
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Yamanaka M, Sakuma M, Matsushita A, Tanaka S, Yamamoto Y, Asai T, Arai H. The Effects of Long-Term Dietary Therapy on Patients with Hypertriglyceridemia. J Atheroscler Thromb 2018; 26:39-49. [PMID: 29794409 PMCID: PMC6308261 DOI: 10.5551/jat.42440] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: This study aimed to evaluate the effect of diet on serum lipids and to assess the effectiveness of long-term dietary therapy for hypertriglyceridemia. Methods: Seventy-nine patients (34 males and 45 females) with hypertriglyceridemia were enrolled and underwent dietary counseling for 12 months based on the following three recommendations: (1) reduce carbohydrate intake, (2) increase n-3 polyunsaturated fatty acid (PUFA) intake, and (3) limit alcohol drinking. We examined the effect of dietary therapy for 6 months on serum triglyceride (TG) levels and also compared the effectiveness of dietary and combined drug therapies on preventing arteriosclerotic disease from 7 to 12 months. Results: We observed that serum TG levels of the patients receiving dietary counseling were decreased compared with baseline at 6 months. Body weight and serum TG levels were decreased, and serum high-density lipoprotein levels were increased in the dietary therapy alone group, whereas BW, body mass index, and abdominal circumference were decreased in the combined drug treatment group compared with baselines at 6 and 12 months. Furthermore, the dietary therapy alone group demonstrated reductions in intake of total energy, carbohydrate, and saturated fatty acids, as well as n-6/n-3 PUFA ratio compared with baselines, but only n-6/n-3 PUFA ratio was decreased in the combined drug treatment group. Conclusion: This study demonstrated a decrease in serum TG level after 12 months of dietary therapy similar to drug therapy, which suggests that it is an effective treatment for hypertriglyceridemia, and heightened awareness should be made to encourage its use. The clinical trial registration number: UMIN000028860.
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Affiliation(s)
- Mizuki Yamanaka
- Laboratory of Clinical Nutrition and Management, School of Food and Nutritional Sciences, The University of Shizuoka
| | - Masae Sakuma
- Laboratory of Clinical Nutrition and Management, School of Food and Nutritional Sciences, The University of Shizuoka
| | - Asami Matsushita
- Laboratory of Clinical Nutrition and Management, School of Food and Nutritional Sciences, The University of Shizuoka
| | - Satomi Tanaka
- Laboratory of Clinical Nutrition and Management, School of Food and Nutritional Sciences, The University of Shizuoka
| | | | | | - Hidekazu Arai
- Laboratory of Clinical Nutrition and Management, School of Food and Nutritional Sciences, The University of Shizuoka
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21
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Schleicher J, Dahmen U, Guthke R, Schuster S. Zonation of hepatic fat accumulation: insights from mathematical modelling of nutrient gradients and fatty acid uptake. J R Soc Interface 2018; 14:rsif.2017.0443. [PMID: 28835543 DOI: 10.1098/rsif.2017.0443] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 07/28/2017] [Indexed: 02/07/2023] Open
Abstract
Intrinsic of non-alcoholic fatty liver diseases is an aberrant accumulation of triglycerides (steatosis), which occurs inhomogeneously within lobules. To improve our understanding of the mechanisms involved in this zonation patterning, we developed a mathematical multicompartment model of hepatic fatty acid metabolism accompanied by blood flow simulations. A model analysis determines the influence of the uptake process of fatty acids, the porto-central gradient of plasma fatty acid concentration, and the oxygen supply via blood on the zonation of triglyceride accumulation. From this theoretical perspective, the plasma oxygen gradient, but not the fatty acid gradient, leads the way to a zonated triglyceride accumulation by its decisive role in oxidative processes. In addition, the uptake mechanism of fatty acids seems to be fundamental for a pericentral dominance of steatosis. However, the mechanism of cellular fatty acid uptake from the blood is still under debate. Our theoretical approach supports the transporter-mediated uptake mechanism and reveals that the maximal velocity of fatty acid uptake affects the switching between a periportal and a pericentral triglyceride accumulation. Further research on hepatic fatty acid uptake is needed to push forward our understanding of aberrant triglyceride accumulation in diet-induced steatosis.
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Affiliation(s)
- Jana Schleicher
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany .,Department of Bioinformatics, Friedrich-Schiller-University Jena, Jena, Germany
| | - Uta Dahmen
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany
| | - Reinhard Guthke
- Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Jena, Germany
| | - Stefan Schuster
- Department of Bioinformatics, Friedrich-Schiller-University Jena, Jena, Germany
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22
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Effect of high chronic intake of sucrose on liver metabolism in aging rats. Modulation by rutin and micronutrients. J Physiol Biochem 2018; 74:569-577. [DOI: 10.1007/s13105-018-0628-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 04/03/2018] [Indexed: 12/29/2022]
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23
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Damiano F, Testini M, Tocci R, Gnoni GV, Siculella L. Translational control of human acetyl-CoA carboxylase 1 mRNA is mediated by an internal ribosome entry site in response to ER stress, serum deprivation or hypoxia mimetic CoCl 2. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:388-398. [PMID: 29343429 DOI: 10.1016/j.bbalip.2018.01.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 01/09/2018] [Accepted: 01/12/2018] [Indexed: 12/12/2022]
Abstract
Acetyl-CoA carboxylase 1 (ACC1) is a cytosolic enzyme catalyzing the rate limiting step in de novo fatty acid biosynthesis. There is mounting evidence showing that ACC1 is susceptible to dysregulation and that it is over-expressed in liver diseases associated with lipid accumulation and in several cancers. In the present study, ACC1 regulation at the translational level is reported. Using several experimental approaches, the presence of an internal ribosome entry site (IRES) has been established in the 5' untranslated region (5' UTR) of the ACC1 mRNA. Transfection experiments with the ACC1 5' UTR inserted in a dicistronic reporter vector show a remarkable increase in the downstream cistron translation, through a cap-independent mechanism. The endoplasmic reticulum (ER) stress condition and the related unfolded protein response (UPR), triggered by treatment with thapsigargin and tunicamycin, cause an increase of the cap-independent translation of ACC1 mRNA in HepG2 cells, despite the overall reduction in global protein synthesis. Other stress conditions, such as serum starvation and incubation with hypoxia mimetic agent CoCl2, up-regulate ACC1 expression in HepG2 cells at the translational level. Overall, these findings indicate that the presence of an IRES in the ACC1 5' UTR allows ACC1 mRNA translation in conditions that are inhibitory to cap-dependent translation. A potential involvement of the cap-independent translation of ACC1 in several pathologies, such as obesity and cancer, has been discussed.
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Affiliation(s)
- Fabrizio Damiano
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Mariangela Testini
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Romina Tocci
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Hammersmith Hospital, London, UK
| | - Gabriele V Gnoni
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Luisa Siculella
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.
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24
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Merola N, Castillo J, Benavente-García O, Ros G, Nieto G. The Effect of Consumption of Citrus Fruit and Olive Leaf Extract on Lipid Metabolism. Nutrients 2017; 9:E1062. [PMID: 28954421 PMCID: PMC5691679 DOI: 10.3390/nu9101062] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 08/30/2017] [Accepted: 09/19/2017] [Indexed: 11/25/2022] Open
Abstract
Citrus fruit and olive leaves are a source of bioactive compounds such as biophenols which have been shown to ameliorate obesity-related conditions through their anti-hyperlipidemic and anti-inflammatory effect, and by regulating lipoproteins and cholesterol body levels. Citrolive™ is a commercial extract which is obtained from the combination of both citrus fruit and olive leaf extracts; hence, it is hypothesised that Citrolive™ may moderate metabolic disorders that are related to obesity and their complications. Initially, an in vitro study of the inhibition of pancreatic lipase activity was made, however, no effect was found. Both preliminary and long-term evaluations of Citrolive™ on lipid metabolism were conducted in an animal model using Wistar rats. In the preliminary in vivo screening, Citrolive™ was tested on postprandial plasma triglyceride level after the administration of an oil emulsion, and a significant reduction in postprandial triacylglycerol (TAG) levels was observed. In the long-term study, Citrolive™ was administered for 60 days on Wistar rats that were fed a high-fat diet. During the study, several associated lipid metabolism indicators were analysed in blood and faeces. At the end of the experiment, the livers were removed and weighed for group comparison. Citrolive™ treatment significantly reduced the liver-to-body-weight ratio, as supported by reduced plasma transaminases compared with control, but insignificantly reduced plasma low density lipoprotein (LDL) and postprandial TAG plasma levels. In addition, faecal analysis showed that the treatment significantly increased total cholesterol excretion. On the other hand, no effect was found on faecal TAG and pancreatic lipase in vitro. In conclusion, treatment ameliorates liver inflammation symptoms that are worsened by the effects of high fat diet.
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Affiliation(s)
- Nicola Merola
- Department of Food Technology, Nutrition and Food Science, Veterinary Faculty University of Murcia, Campus de Espinardo, 30100 Espinardo, Murcia, Spain.
| | - Julián Castillo
- Research and Development Department of Nutrafur-Frutarom Group, Camino Viejo de Pliego s/n, 80320 Alcantarilla, Murcia, Spain.
| | - Obdulio Benavente-García
- Research and Development Department of Nutrafur-Frutarom Group, Camino Viejo de Pliego s/n, 80320 Alcantarilla, Murcia, Spain.
| | - Gaspar Ros
- Department of Food Technology, Nutrition and Food Science, Veterinary Faculty University of Murcia, Campus de Espinardo, 30100 Espinardo, Murcia, Spain.
| | - Gema Nieto
- Department of Food Technology, Nutrition and Food Science, Veterinary Faculty University of Murcia, Campus de Espinardo, 30100 Espinardo, Murcia, Spain.
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25
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Ferramosca A, Di Giacomo M, Zara V. Antioxidant dietary approach in treatment of fatty liver: New insights and updates. World J Gastroenterol 2017; 23:4146-4157. [PMID: 28694655 PMCID: PMC5483489 DOI: 10.3748/wjg.v23.i23.4146] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 02/22/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols (i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids (i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates (i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.
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26
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Ferramosca A, Moscatelli N, Di Giacomo M, Zara V. Dietary fatty acids influence sperm quality and function. Andrology 2017; 5:423-430. [PMID: 28334508 DOI: 10.1111/andr.12348] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 12/08/2016] [Accepted: 12/14/2016] [Indexed: 01/07/2023]
Abstract
Recently, obesity has been linked to male infertility. In animal models the administration of a high-fat diet caused a reduction in sperm quality, by impairing gamete energy metabolism. The aim of this study was to investigate a possible effect of dietary fatty acids supplementation in the modulation of sperm energy metabolism and, in turn, in the improvement of sperm quality in rats fed a high-fat diet. Sexually mature male Sprague-Dawley rats were divided into four groups and fed for 4 weeks a standard diet (control group), a high-fat diet (enriched in 35% of fat and 15% sucrose), a high-fat diet supplemented with 2.5% olive oil (a source of monounsaturated fatty acids) or a high-fat diet supplemented with 2.5% krill oil (a source of n-3 polyunsaturated fatty acids). Liver and adipose tissue weight, plasma glucose, insulin and lipid concentrations were determined. Activities of enzymes involved in sperm energetic metabolism were evaluated by spectrophotometric assays. Sperm mitochondrial respiratory efficiency was also assayed. The obtained results suggest that olive oil partially counteracts the negative effects of a high-fat diet on sperm quality, by increasing gamete motility, by reducing oxidative stress and slightly improving mitochondrial respiration efficiency. On the other hand, krill oil determines an increase in sperm concentration and motility, an increase in the activities of lactate dehydrogenase, Krebs cycle enzymes and respiratory chain complexes; a parallel increase in the cellular levels of ATP and a reduction in oxidative damage were also observed. These results suggest that dietary fatty acids are able to positively influence sperm quality and function.
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Affiliation(s)
- A Ferramosca
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce, Italy.,Center for Biomolecular Nanotechnologies @UNILE, Istituto Italiano di Tecnologia, Arnesano (LE), Italy
| | - N Moscatelli
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce, Italy.,Center for Biomolecular Nanotechnologies @UNILE, Istituto Italiano di Tecnologia, Arnesano (LE), Italy
| | - M Di Giacomo
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce, Italy
| | - V Zara
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce, Italy
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27
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Reynés B, Palou M, Palou A. Gene expression modulation of lipid and central energetic metabolism related genes by high-fat diet intake in the main homeostatic tissues. Food Funct 2017; 8:629-650. [DOI: 10.1039/c6fo01473a] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
HF diet feeding affects the energy balance by transcriptional metabolic adaptations, based in direct gene expression modulation, perinatal programing and transcriptional factor regulation, which could be affected by the animal model, gender or period of dietary treatment.
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Affiliation(s)
- Bàrbara Reynés
- Laboratory of Molecular Biology
- Nutrition and Biotechnology
- Universitat de les Illes Balears and CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn)
- Palma de Mallorca
- Spain
| | - Mariona Palou
- Alimentómica SL (Spin off no. 001 from UIB)
- Palma Mallorca
- Spain
| | - Andreu Palou
- Laboratory of Molecular Biology
- Nutrition and Biotechnology
- Universitat de les Illes Balears and CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn)
- Palma de Mallorca
- Spain
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28
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A possible link between hepatic mitochondrial dysfunction and diet-induced insulin resistance. Eur J Nutr 2016; 55:1-6. [PMID: 26476631 DOI: 10.1007/s00394-015-1073-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 10/08/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Mitochondria are the main cellular sites devoted to ATP production and lipid oxidation. Therefore, the mitochondrial dysfunction could be an important determinant of cellular fate of circulating lipids, that accumulate in the cytoplasm, if they are not oxidized. The ectopic fat accumulation is associated with the development of insulin resistance, and a link between mitochondrial dysfunction and insulin resistance has been proposed. METHODS Recent data on the possible link existing between mitochondrial dysfunction in the liver and diet induced obesity will be summarized, focusing on the three factors that affect the mitochondrial oxidation of metabolic fuels, i.e. organelle number, organelle activity, and energetic efficiency of the mitochondrial machinery in synthesizing ATP. Search in PubMed relevant articles from 2003 to 2014 was conducted, by using query “liver mitochondria and obesity” “hepatic mitochondria and obesity” “liver mitochondria and high fat diet” and “hepatic mitochondria and high fat diet” and including related articles by the same groups. RESULTS Several works, by using different physiological approaches, have dealt with alteration in mitochondrial function in obesity and diabetes. Most results show that hepatic mitochondrial function is impaired in models of obesity and insulin resistance induced by high-fat or highfructose feeding. CONCLUSIONS Since mitochondria are the main producers of both cellular energy and free radicals, dysfunctional mitochondria could play an important role in the development of insulin resistance and ectopic fat storage in the liver, thus supporting the emerging idea that mitochondrial dysfunction is closely related to the development of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis.
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29
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Giudetti AM, Stanca E, Siculella L, Gnoni GV, Damiano F. Nutritional and Hormonal Regulation of Citrate and Carnitine/Acylcarnitine Transporters: Two Mitochondrial Carriers Involved in Fatty Acid Metabolism. Int J Mol Sci 2016; 17:ijms17060817. [PMID: 27231907 PMCID: PMC4926351 DOI: 10.3390/ijms17060817] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 05/06/2016] [Accepted: 05/19/2016] [Indexed: 12/13/2022] Open
Abstract
The transport of solutes across the inner mitochondrial membrane is catalyzed by a family of nuclear-encoded membrane-embedded proteins called mitochondrial carriers (MCs). The citrate carrier (CiC) and the carnitine/acylcarnitine transporter (CACT) are two members of the MCs family involved in fatty acid metabolism. By conveying acetyl-coenzyme A, in the form of citrate, from the mitochondria to the cytosol, CiC contributes to fatty acid and cholesterol synthesis; CACT allows fatty acid oxidation, transporting cytosolic fatty acids, in the form of acylcarnitines, into the mitochondrial matrix. Fatty acid synthesis and oxidation are inversely regulated so that when fatty acid synthesis is activated, the catabolism of fatty acids is turned-off. Malonyl-CoA, produced by acetyl-coenzyme A carboxylase, a key enzyme of cytosolic fatty acid synthesis, represents a regulator of both metabolic pathways. CiC and CACT activity and expression are regulated by different nutritional and hormonal conditions. Defects in the corresponding genes have been directly linked to various human diseases. This review will assess the current understanding of CiC and CACT regulation; underlining their roles in physio-pathological conditions. Emphasis will be placed on the molecular basis of the regulation of CiC and CACT associated with fatty acid metabolism.
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Affiliation(s)
- Anna M Giudetti
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce 73100, Italy.
| | - Eleonora Stanca
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce 73100, Italy.
| | - Luisa Siculella
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce 73100, Italy.
| | - Gabriele V Gnoni
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce 73100, Italy.
| | - Fabrizio Damiano
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce 73100, Italy.
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30
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Ferramosca A, Conte A, Moscatelli N, Zara V. A high-fat diet negatively affects rat sperm mitochondrial respiration. Andrology 2016; 4:520-5. [DOI: 10.1111/andr.12182] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 02/08/2016] [Accepted: 02/18/2016] [Indexed: 01/08/2023]
Affiliation(s)
- A. Ferramosca
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali; Università del Salento; Lecce Italy
| | - A. Conte
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali; Università del Salento; Lecce Italy
| | - N. Moscatelli
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali; Università del Salento; Lecce Italy
| | - V. Zara
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali; Università del Salento; Lecce Italy
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31
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Lipid accumulation stimulates the cap-independent translation of SREBP-1a mRNA by promoting hnRNP A1 binding to its 5'-UTR in a cellular model of hepatic steatosis. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:471-81. [PMID: 26869449 DOI: 10.1016/j.bbalip.2016.02.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 02/03/2016] [Accepted: 02/06/2016] [Indexed: 12/14/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic disease characterized by accumulation of lipid droplets in hepatocytes. Enhanced release of non-esterified fatty acids from adipose tissue accounts for a remarkable fraction of accumulated lipids. However, the de novo lipogenesis (DNL) is also implicated in the etiology of the NAFLD. Sterol Regulatory Element-Binding Protein-1 (SREBP-1) is a transcription factor modulating the expression of several lipogenic enzymes. In the present study, in order to investigate the effect of lipid droplet accumulation on DNL, we used a cellular model of steatosis represented by HepG2 cells cultured in a medium supplemented with free oleic and palmitic fatty acids (FFAs). We report that FFA supplementation induces the expression of genes coding for enzymes involved in the DNL as well as for the transcription factor SREBP-1a. The SREBP-1a mRNA translation, dependent on an internal ribosome entry site (IRES), and the SREBP-1a proteolytic cleavage are activated by FFAs. Furthermore, FFA treatment enhances the expression and the nucleus-cytosolic shuttling of hnRNP A1, a trans-activating factor of SREBP-1a IRES. The binding of hnRNP A1 to the SREBP-1a IRES is also increased upon FFA supplementation. The relocation of hnRNP A1 and the consequent increase of SREBP-1a translation are dependent on the p38 MAPK signal pathway, which is activated by FFAs. By RNA interference approach, we demonstrate that hnRNP A1 is implicated in the FFA-induced expression of SREBP-1a and of its target genes as well as in the lipid accumulation in cells.
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32
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Somvanshi PR, Patel AK, Bhartiya S, Venkatesh KV. Influence of plasma macronutrient levels on hepatic metabolism: role of regulatory networks in homeostasis and disease states. RSC Adv 2016. [DOI: 10.1039/c5ra18128c] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Multilevel regulations by metabolic, signaling and transcription pathways form a complex network that works to provide robust metabolic regulation in the liver. This analysis indicates that dietary perturbations in these networks can lead to insulin resistance.
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Affiliation(s)
- Pramod R. Somvanshi
- Biosystems Engineering Lab
- Department of Chemical Engineering
- Indian Institute of Technology Bombay
- Mumbai
- India 400076
| | - Anilkumar K. Patel
- Biosystems Engineering Lab
- Department of Chemical Engineering
- Indian Institute of Technology Bombay
- Mumbai
- India 400076
| | - Sharad Bhartiya
- Control Systems Engineering Lab
- Department of Chemical Engineering
- Indian Institute of Technology Bombay
- Mumbai
- India 400076
| | - K. V. Venkatesh
- Biosystems Engineering Lab
- Department of Chemical Engineering
- Indian Institute of Technology Bombay
- Mumbai
- India 400076
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33
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Bonacic K, Estévez A, Bellot O, Conde-Sieira M, Gisbert E, Morais S. Dietary Fatty Acid Metabolism is Affected More by Lipid Level than Source in Senegalese Sole Juveniles: Interactions for Optimal Dietary Formulation. Lipids 2015; 51:105-22. [PMID: 26563870 DOI: 10.1007/s11745-015-4089-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 10/19/2015] [Indexed: 01/17/2023]
Abstract
This study analyses the effects of dietary lipid level and source on lipid absorption and metabolism in Senegalese sole (Solea senegalensis). Juvenile fish were fed 4 experimental diets containing either 100 % fish oil (FO) or 25 % FO and 75 % vegetable oil (VO; rapeseed, linseed and soybean oils) at two lipid levels (~8 or ~18 %). Effects were assessed on fish performance, body proximate composition and lipid accumulation, activity of hepatic lipogenic and fatty acid oxidative enzymes and, finally, on the expression of genes related to lipid metabolism in liver and intestine, and to intestinal absorption, both pre- and postprandially. Increased dietary lipid level had no major effects on growth and feeding performance (FCR), although fish fed FO had marginally better growth. Nevertheless, diets induced significant changes in lipid accumulation and metabolism. Hepatic lipid deposits were higher in fish fed VO, associated to increased hepatic ATP citrate lyase activity and up-regulated carnitine palmitoyltransferase 1 (cpt1) mRNA levels post-prandially. However, lipid level had a larger effect on gene expression of metabolic (lipogenesis and β-oxidation) genes than lipid source, mostly at fasting. High dietary lipid level down-regulated fatty acid synthase expression in liver and intestine, and increased cpt1 mRNA in liver. Large lipid accumulations were observed in the enterocytes of fish fed high lipid diets. This was possibly a result of a poor capacity to adapt to high dietary lipid level, as most genes involved in intestinal absorption were not regulated in response to the diet.
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Affiliation(s)
- Kruno Bonacic
- IRTA, Centre de Sant Carles de la Ràpita (SCR), Ctra. Poble Nou km 5.5, 43540, Tarragona, Spain.
| | - Alicia Estévez
- IRTA, Centre de Sant Carles de la Ràpita (SCR), Ctra. Poble Nou km 5.5, 43540, Tarragona, Spain.
| | - Olga Bellot
- IRTA, Centre de Sant Carles de la Ràpita (SCR), Ctra. Poble Nou km 5.5, 43540, Tarragona, Spain.
| | - Marta Conde-Sieira
- CIMAR/CIIMAR, Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Rua dos Bragas, 289, 4050-123, Porto, Portugal.
- Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, 36310, Vigo, Spain.
| | - Enric Gisbert
- IRTA, Centre de Sant Carles de la Ràpita (SCR), Ctra. Poble Nou km 5.5, 43540, Tarragona, Spain.
| | - Sofia Morais
- IRTA, Centre de Sant Carles de la Ràpita (SCR), Ctra. Poble Nou km 5.5, 43540, Tarragona, Spain.
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34
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Krill Oil Ameliorates Mitochondrial Dysfunctions in Rats Treated with High-Fat Diet. BIOMED RESEARCH INTERNATIONAL 2015; 2015:645984. [PMID: 26301251 PMCID: PMC4537729 DOI: 10.1155/2015/645984] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 12/09/2014] [Accepted: 01/11/2015] [Indexed: 12/29/2022]
Abstract
In recent years, several studies focused their attention on the role of dietary fats in the pathogenesis of hepatic steatosis. It has been demonstrated that a high-fat diet is able to induce hyperglycemia, hyperinsulinemia, obesity, and nonalcoholic fatty liver disease. On the other hand, krill oil, a novel dietary supplement of n-3 PUFAs, has the ability to improve lipid and glucose metabolism, exerting possible protective effects against hepatic steatosis. In this study we have investigated the effects of krill oil on mitochondrial energetic metabolism in animals fed a high-fat diet. To this end, male Sprague-Dawley rats were divided into three groups and fed for 4 weeks with a standard diet (control group), a diet with 35% fat (HF group), or a high-fat diet supplemented with 2.5% krill oil (HF+KO group). The obtained results suggest that krill oil promotes the burning of fat excess introduced by the high-fat diet. This effect is obtained by stimulating mitochondrial metabolic pathways such as fatty acid oxidation, Krebs cycle, and respiratory chain complexes activity. Modulation of the expression of carrier proteins involved in mitochondrial uncoupling was also observed. Overall, krill oil counteracts the negative effects of a high-fat diet on mitochondrial energetic metabolism.
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35
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Maniam J, Antoniadis CP, Morris MJ. The effect of early-life stress and chronic high-sucrose diet on metabolic outcomes in female rats. Stress 2015; 18:524-37. [PMID: 26365331 DOI: 10.3109/10253890.2015.1079617] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Early-life stress affects metabolic outcomes and choice of diet influences the development of metabolic disease. Here we tested the hypothesis that chronic sugar intake exacerbates metabolic deficits induced by early-life stress. Early-life stress was induced in Sprague-Dawley rats using limited nesting material in early lactation (LN, postnatal days 2-9), and siblings were given chow alone or with additional sucrose post weaning (n = 9-17 per group). Female control and LN siblings had unlimited access to either chow plus water, or chow and water plus 25% sucrose solution (Sucrose), from 3-15 weeks of age. Weekly body weight and food intake were measured. Glucose and insulin tolerance were tested at 13 and 14 weeks of age, respectively. Rats were killed at 15 weeks. Hepatic triglyceride and markers of lipid synthesis - fatty acid synthase, acetyl-CoA carboxylase alpha and oxidation - and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α) were examined. Mediators of hepatic glucocorticoid metabolism, specifically 11-beta hydroxysteroid dehydrogenase-1 (11βHSD-1), 5-α reductase, and glucocorticoid and mineralocorticoid receptor mRNAs were also measured. Sucrose increased caloric intake in both groups, but overall energy intake was not altered by LN exposure. LN exposure had no further impact on sucrose-induced glucose intolerance and increased plasma and liver triglycerides. Hepatic markers of fat synthesis and oxidation were concomitantly activated and 11βHSD-1 mRNA expression was increased by 53% in LN-Sucrose versus Con-Sucrose rats. Adiposity was increased by 26% in LN-Sucrose versus Con-Sucrose rats. Thus, LN exposure had minimal adverse metabolic effects despite high-sugar diet postweaning.
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MESH Headings
- 11-beta-Hydroxysteroid Dehydrogenase Type 1/drug effects
- 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics
- 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/drug effects
- 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics
- Acetyl-CoA Carboxylase
- Adiposity/drug effects
- Animals
- Blood Glucose/drug effects
- Blood Glucose/metabolism
- Body Weight
- Diet
- Dietary Sucrose/pharmacology
- Eating/drug effects
- Eating/psychology
- Energy Intake/drug effects
- Fatty Acid Synthase, Type I/drug effects
- Fatty Acid Synthase, Type I/metabolism
- Feeding Behavior/drug effects
- Feeding Behavior/psychology
- Female
- Lipogenesis
- Liver/metabolism
- Obesity/metabolism
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- RNA, Messenger/drug effects
- RNA, Messenger/metabolism
- Rats
- Rats, Sprague-Dawley
- Receptors, Glucocorticoid/drug effects
- Receptors, Glucocorticoid/genetics
- Receptors, Mineralocorticoid/drug effects
- Receptors, Mineralocorticoid/genetics
- Stress, Psychological/metabolism
- Stress, Psychological/psychology
- Transcription Factors/drug effects
- Transcription Factors/metabolism
- Triglycerides/metabolism
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Affiliation(s)
- Jayanthi Maniam
- a Department of Pharmacology , School of Medical Sciences , UNSW Australia, UNSW Sydney , New South Wales , Australia
| | - Christopher P Antoniadis
- a Department of Pharmacology , School of Medical Sciences , UNSW Australia, UNSW Sydney , New South Wales , Australia
| | - Margaret J Morris
- a Department of Pharmacology , School of Medical Sciences , UNSW Australia, UNSW Sydney , New South Wales , Australia
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Berge K, Robertson B, Burri L. Safety assessment of Superba™ krill powder: Subchronic toxicity study in rats. Toxicol Rep 2014; 2:144-151. [PMID: 28962346 PMCID: PMC5598319 DOI: 10.1016/j.toxrep.2014.11.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 11/04/2014] [Accepted: 11/11/2014] [Indexed: 11/21/2022] Open
Abstract
The safety of krill powder was assessed in a subchronic 13-week toxicity study where rats were fed krill powder or control diets. The krill powder inclusion in the test diet was 9.67% (w/w). There were no differences noted in body weight or food consumption in either gender. Differences in clinical chemistry values were noted in the krill powder-treated animals, but these findings were of no toxicological significance. A significant decrease in absolute heart weight, but not relative heart weight, was observed in both sexes given krill powder, although no corresponding histological changes were observed. Hepatocyte vacuolation was noted histologically in males fed krill powder. This finding was not associated with other indications of hepatic dysfunction. The no observed adverse effect level (NOAEL) for the conditions of this study was considered to be 9.67% krill powder.
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Affiliation(s)
- Kjetil Berge
- Aker BioMarine Antarctic AS, Fjordalléen 16, PO Box 1423 Vika, NO-0115 Oslo, Norway
| | | | - Lena Burri
- Aker BioMarine Antarctic AS, Fjordalléen 16, PO Box 1423 Vika, NO-0115 Oslo, Norway
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37
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Damiano F, Tocci R, Gnoni GV, Siculella L. Expression of citrate carrier gene is activated by ER stress effectors XBP1 and ATF6α, binding to an UPRE in its promoter. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1849:23-31. [PMID: 25450523 DOI: 10.1016/j.bbagrm.2014.10.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 10/17/2014] [Accepted: 10/21/2014] [Indexed: 01/04/2023]
Abstract
The Unfolded Protein Response (UPR) is an intracellular signaling pathway which is activated when unfolded or misfolded proteins accumulate in the Endoplasmic Reticulum (ER), a condition commonly referred to as ER stress. It has been shown that lipid biosynthesis is increased in ER-stressed cells. The N(ε)-lysine acetylation of ER-resident proteins, including chaperones and enzymes involved in the post-translational protein modification and folding, occurs upon UPR activation. In both ER proteins acetylation and lipid synthesis, acetyl-CoA is the donor of acetyl group and it is transported from the cytosol into the ER. The cytosolic pool of acetyl-CoA is mainly derived from the activity of mitochondrial citrate carrier (CiC). Here, we have demonstrated that expression of CiC is activated in human HepG2 and rat BRL-3A cells during tunicamycin-induced ER stress. This occurs through the involvement of an ER stress responsive region identified within the human and rat CiC proximal promoter. A functional Unfolded Protein Response Element (UPRE) confers responsiveness to the promoter activation by UPR transducers ATF6α and XBP1. Overall, our data demonstrate that CiC expression is activated during ER stress through the binding of ATF6α and XBP1 to an UPRE element located in the proximal promoter of Cic gene. The role of ER stress-mediated induction of CiC expression has been discussed.
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Affiliation(s)
- Fabrizio Damiano
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy.
| | - Romina Tocci
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy
| | - Gabriele Vincenzo Gnoni
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy
| | - Luisa Siculella
- Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy
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Robertson B, Burri L, Berge K. Genotoxicity test and subchronic toxicity study with Superba™ krill oil in rats. Toxicol Rep 2014; 1:764-776. [PMID: 28962289 PMCID: PMC5598210 DOI: 10.1016/j.toxrep.2014.07.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 07/08/2014] [Accepted: 07/08/2014] [Indexed: 11/26/2022] Open
Abstract
The safety of krill oil was assessed in a subchronic toxicity study and in a genotoxicity test. In a 13-week study, rats were fed krill oil or control diets. There were no differences noted in body weight, food consumption or in the functional observation battery parameters in either gender. Differences in both haematology and clinical chemistry values were noted in the krill oil-treated groups. However these findings were of no toxicological significance. Significant decreases in absolute and covariant heart weight in some krill oil-treated animals were noted although no corresponding histological changes were observed. In addition, periportal microvesicular hepatocyte vacuolation was noted histologically in males fed 5% krill oil. This finding was not associated with other indications of hepatic dysfunction. Given that the effects of the 13-week toxicity study were non-toxic in nature, the no observed adverse effect level (NOAEL) for the conditions of this study was considered to be 5% krill oil. The genotoxicity experiments documented no mutagenicity of krill oil in bacteria.
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Affiliation(s)
| | - Lena Burri
- Aker BioMarine Antarctic AS, Fjordalléen 16, PO Box 1423 Vika, NO-0115 Oslo, Norway
| | - Kjetil Berge
- Aker BioMarine Antarctic AS, Fjordalléen 16, PO Box 1423 Vika, NO-0115 Oslo, Norway
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Rosso N, Chavez-Tapia NC, Tiribelli C, Bellentani S. Translational approaches: From fatty liver to non-alcoholic steatohepatitis. World J Gastroenterol 2014; 20:9038-9049. [PMID: 25083077 PMCID: PMC4112858 DOI: 10.3748/wjg.v20.i27.9038] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 12/04/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
Over the past few decades, non-alcoholic fatty liver disease (NAFLD) has become one, if not the most common, cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis.
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Ferramosca A, Zara V. Dietary fat and hepatic lipogenesis: mitochondrial citrate carrier as a sensor of metabolic changes. Adv Nutr 2014; 5:217-25. [PMID: 24829468 PMCID: PMC4013174 DOI: 10.3945/an.113.004762] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Citrate carrier (CIC) is an integral protein of the inner mitochondrial membrane that has a fundamental role in hepatic intermediary metabolism. Its primary function is to catalyze the transport of citrate from mitochondria, where this molecule is formed, to cytosol, where this molecule is used for fatty acid (FA) and cholesterol synthesis. Therefore, mitochondrial CIC acts upstream of cytosolic lipogenic reactions, and its regulation is particularly important in view of the modulation of hepatic lipogenesis. Although a great deal of data are currently available on the dietary modulation of cytosolic lipogenic enzymes, little is known about the nutritional regulation of CIC transport activity. In this review, we describe the differential effects of distinct FAs present in the diet on the activity of mitochondrial CIC. In particular, polyunsaturated FAs were powerful modulators of the activity of mitochondrial CIC by influencing its expression through transcriptional and posttranscriptional mechanisms. On the contrary, saturated and monounsaturated FAs did not influence mitochondrial CIC activity. Moreover, variations in CIC activity were connected to similar alterations in the metabolic pathways to which the transported citrate is channeled. Therefore, CIC may be considered as a sensor for changes occurring inside the hepatocyte and may represent an important target for the regulation of hepatic lipogenesis. The crucial role of this protein is reinforced by the recent discovery of its involvement in other cellular processes, such as glucose-stimulated insulin secretion, inflammation, tumorigenesis, genome stability, and sperm metabolism.
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Affiliation(s)
| | - Vincenzo Zara
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
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