Fatty Acids, Genes and Microbiota in Fatty Liver
10 maj 2016 uppdaterad av: Johane Allard
Non-alcoholic Steatohepatitis Versus Simple Hepatic Steatosis: Is There a Difference in the Nutritional Factors Influencing Lipid Perioxidation and Inflammation?
The first aim of this study is to assess oxidative stress and nutritional status in patients with elevated liver enzymes who were found to have either simple steatosis (SS) or nonalcoholic steatohepatitis (NASH) or normal histological findings on liver biopsy by measuring liver lipid peroxides and tumor necrosis factor (TNF)-α, liver pathology and immunohistochemistry, liver function tests, liver and red blood cell membrane fatty composition, insulin resistance (IR) parameters, plasma lipid peroxides, plasma antioxidant vitamins and antioxidant power, lipid profile, subject demographics, medical history and medication use.
The second aim is to detect differences in hepatic gene expression (messenger RNA, mRNA) and epigenetic regulation (micro RNA, miRNA) between patients with SS or NASH and healthy controls, in addition to determine in patients with non-alcoholic fatty liver disease (NAFLD = SS+NASH combined) whether there is an association between hepatic n-3 PUFA content and gene expression.
The third aim is to determine the intestinal microbiome (microbial composition and metagenome) in patients with SS or NASH and healthy controls.
Studieöversikt
Status
Avslutad
Detaljerad beskrivning
NASH is associated with obesity, diabetes and hyperlipidemia. Fat accumulation in the liver is likely due to variable degrees of disordered fatty-acid metabolism and insulin resistance (IR). Liver steatosis, especially polyunsaturated fatty acids (PUFA) in the liver, increases lipid peroxidation and is associated with a reduction in the antioxidant defense system. This oxidative stress can lead to increased production of pro-inflammatory cytokines (TNF-α, transforming growth factor-beta) contributing to the development of steatohepatitis and fibrosis.TNF-α - may further contribute to IR. In addition, changes in fatty acid composition within the liver may influence lipid metabolism and inflammation. In particular, n-3 PUFA have an effect on the insulin sensitivity, transcription of antioxidant genes, inflammatory response and production of reactive oxygen species. Differences might be seen on the gene expression level (mRNA) and also in epigenetic regulation (miRNA).
Microbiota composition might influence energy metabolism, and inflammatory tone and IR through increased endotoxemia and therefore could also play a role in the development of NAFLD.
Studietyp
Observationell
Inskrivning (Faktisk)
205
Kontakter och platser
Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.
Studieorter
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Ontario
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Toronto, Ontario, Kanada, M5G 1Z5
- Toronto General Hospital
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Deltagandekriterier
Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.
Urvalskriterier
Åldrar som är berättigade till studier
18 år till 70 år (Vuxen, Äldre vuxen)
Tar emot friska volontärer
Nej
Kön som är behöriga för studier
Allt
Testmetod
Icke-sannolikhetsprov
Studera befolkning
Healthy living liver donors from the Multiorgan transplant program at the University Health Network Patients with nonalcoholic fatty liver disease (SS or NASH on liver biopsy) or patients with elevated liver enzymes but no significant findings on liver biopsy.
Beskrivning
Inclusion criteria:
- Male and female patients, age >18 y
- A liver biopsy with a diagnosis of SS or NASH OR No signs of steatosis, fibrosis or any other kind of liver disease on histology (minimal findings) OR For healthy control subjects, those with normal liver enzymes and normal liver imaging on ultrasound
- alcohol consumption (<20g of ethanol per day);
- absence of any other possible cause for liver dysfunction.
Exclusion criteria:
- any other liver disease apart from NAFLD
- anticipated need for liver transplantation in one year or complications of liver disease;
- any reasons contraindicating a liver biopsy (patients) or liver donation (healthy donors)
- chronic gastrointestinal diseases, previous gastrointestinal surgery modifying the anatomy, patients with diabetes requiring insulin.
- medications known to precipitate steatohepatitis (corticosteroids, high dose estrogens, methotrexate, amiodarone, spironolactone, sulfasalazine, perhexiline maleate, diethylamino- ethoxyhexestrol (DH), tamoxifen, diethylstilbestrol, naproxen or oxacillin) or regular intake of non-steroidal anti-inflammatory drugs (except for low dose aspirin), use of ursodeoxycholic acid or any experimental drug in the 6 months prior to entry.
- regular intake of prebiotics, probiotics, antibiotics, or laxatives; in the 3 months prior to study entry
- Pregnant or lactating
Studieplan
Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.
Hur är studien utformad?
Designdetaljer
- Observationsmodeller: Kohort
- Tidsperspektiv: Tvärsnitt
Kohorter och interventioner
Grupp / Kohort |
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Healthy controls
Healthy living liver donors with healthy liver on imaging and/or liver histology
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Simple steatosis
Patients with non-alcoholic fatty liver disease confirmed by liver biopsy with a diagnosis of simple steatosis
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Nonalcoholic steatohepatitis
Patients with non-alcoholic fatty liver disease confirmed by liver biopsy with a diagnosis of steatohepatitis
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Minimal findings
Patients undergoing liver biopsy because of suspected fatty liver but nonspecific findings on liver histology.
This group was initially used as a control group.
Later in the study, this group was replaced by healthy donors as true healthy controls.
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Vad mäter studien?
Primära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
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Hepatic fatty acid composition in total lipids in liver biopsy
Tidsram: Baseline
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Gas chromatography
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Baseline
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Hepatic gene expression
Tidsram: Baseline
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mRNA by microarray
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Baseline
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Intestinal microbiota composition
Tidsram: Baseline
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Illumina 16S technology
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Baseline
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Sekundära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
|---|---|---|
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Lipid peroxides in the liver
Tidsram: Baseline
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Test kit
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Baseline
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Hepatic liver antioxidant power
Tidsram: Baseline
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Test kit
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Baseline
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Hepatic microRNA expression in the liver
Tidsram: Baseline
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NanoString
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Baseline
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Intestinal microbiota - specific organisms and groups
Tidsram: Baseline
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Quantitative real-time polymerase chain reaction
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Baseline
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Intestinal microbiome on a genetic level
Tidsram: Baseline
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Illumina sequencing technology
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Baseline
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Short-chain fatty acids in stool
Tidsram: Baseline
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Gas chromatography
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Baseline
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Plasma endotoxin
Tidsram: Baseline
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Limulus assay
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Baseline
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Andra resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
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Hepatic phospholipid composition
Tidsram: Baseline
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Gas chromatography
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Baseline
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Red blood cell fatty acid and phospholipid composition
Tidsram: Baseline
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Gas chromatography
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Baseline
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Plasma fatty acid composition
Tidsram: Baseline
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Gas chromatography
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Baseline
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Plasma lipid peroxides
Tidsram: Baseline
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Test kit
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Baseline
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Plasma antioxidant vitamins
Tidsram: Baseline
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Vitamin C colorimetric, alpha- and gamma-tocopherol and beta-carotene by high-performance liquid chromatography
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Baseline
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Serum antioxidant power
Tidsram: Baseline
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Test kit
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Baseline
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TNF-alpha in the liver
Tidsram: Baseline
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Enzyme linked immunosorbent assay
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Baseline
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Immunohistochemistry
Tidsram: Baseline
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Staining for malondialdehyde, alpha-smooth muscle actin, transforming growth factor beta
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Baseline
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Free choline in serum
Tidsram: Baseline
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liquid chromatography/electrospray ionization-isotope dilution mass spectrometry (LC/ESI-IDMS)
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Baseline
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Bacterial DNA in plasma
Tidsram: Baseline
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Quantitative polymerase chain reaction for bacterial 16S rDNA
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Baseline
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Insulin resistance
Tidsram: Baseline
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Fasting glucose and insulin to calculate insulin resistance (HOMA-IR), C-peptide, hemoglobin A1c, all by standard laboratory methods
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Baseline
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Plasma ethanol
Tidsram: Baseline
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standard laboratory measurement
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Baseline
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Anthropometry
Tidsram: Baseline
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Weight, height, skinfolds, bioelectrical impedance analysis
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Baseline
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Food intake
Tidsram: Baseline
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7-day food records
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Baseline
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Physical activity
Tidsram: Baseline
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7 day activity logs
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Baseline
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Factors influencing intestinal microbiota
Tidsram: Baseline
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Environmental questionnaire
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Baseline
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Liver function tests
Tidsram: Baseline
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Alanine transaminase, aspartate transaminase, alkaline phosphatase, standard laboratory tests
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Baseline
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Samarbetspartners och utredare
Det är här du hittar personer och organisationer som är involverade i denna studie.
Sponsor
Samarbetspartners
Utredare
- Huvudutredare: Johane Allard, MD,FRCPC, University Health Network, Toronto
Publikationer och användbara länkar
Den som ansvarar för att lägga in information om studien tillhandahåller frivilligt dessa publikationer. Dessa kan handla om allt som har med studien att göra.
Allmänna publikationer
- Schwenger KJ, Allard JP. Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol. 2014 Feb 21;20(7):1712-23. doi: 10.3748/wjg.v20.i7.1712.
- Monteiro J, Leslie M, Moghadasian MH, Arendt BM, Allard JP, Ma DW. The role of n - 6 and n - 3 polyunsaturated fatty acids in the manifestation of the metabolic syndrome in cardiovascular disease and non-alcoholic fatty liver disease. Food Funct. 2014 Mar;5(3):426-35. doi: 10.1039/c3fo60551e.
- Mouzaki M, Allard JP. The role of nutrients in the development, progression, and treatment of nonalcoholic fatty liver disease. J Clin Gastroenterol. 2012 Jul;46(6):457-67. doi: 10.1097/MCG.0b013e31824cf51e.
- Mouzaki M, Allard J. Non-alcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Ann Gastroenterol. 2012;25(3):207-217.
- Da Silva HE, Arendt BM, Noureldin SA, Therapondos G, Guindi M, Allard JP. A cross-sectional study assessing dietary intake and physical activity in Canadian patients with nonalcoholic fatty liver disease vs healthy controls. J Acad Nutr Diet. 2014 Aug;114(8):1181-94. doi: 10.1016/j.jand.2014.01.009. Epub 2014 Mar 14.
- Arendt BM, Ma DW, Simons B, Noureldin SA, Therapondos G, Guindi M, Sherman M, Allard JP. Nonalcoholic fatty liver disease is associated with lower hepatic and erythrocyte ratios of phosphatidylcholine to phosphatidylethanolamine. Appl Physiol Nutr Metab. 2013 Mar;38(3):334-40. doi: 10.1139/apnm-2012-0261. Epub 2012 Oct 15.
- Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, McGilvray ID, Allard JP. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology. 2013 Jul;58(1):120-7. doi: 10.1002/hep.26319. Epub 2013 May 14.
- Allard JP, Aghdassi E, Mohammed S, Raman M, Avand G, Arendt BM, Jalali P, Kandasamy T, Prayitno N, Sherman M, Guindi M, Ma DW, Heathcote JE. Nutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): a cross-sectional study. J Hepatol. 2008 Feb;48(2):300-7. doi: 10.1016/j.jhep.2007.09.009. Epub 2007 Nov 20.
- Arendt BM, Comelli EM, Ma DW, Lou W, Teterina A, Kim T, Fung SK, Wong DK, McGilvray I, Fischer SE, Allard JP. Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids. Hepatology. 2015 May;61(5):1565-78. doi: 10.1002/hep.27695. Epub 2015 Feb 27.
- Pettinelli P, Arendt BM, Schwenger KJP, Sivaraj S, Bhat M, Comelli EM, Lou W, Allard JP. Relationship Between Hepatic Gene Expression, Intestinal Microbiota, and Inferred Functional Metagenomic Analysis in NAFLD. Clin Transl Gastroenterol. 2022 Jul 1;13(7):e00466. doi: 10.14309/ctg.0000000000000466. Epub 2022 Feb 10.
Studieavstämningsdatum
Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.
Studera stora datum
Studiestart
1 oktober 2003
Primärt slutförande (Faktisk)
1 augusti 2015
Avslutad studie (Faktisk)
1 augusti 2015
Studieregistreringsdatum
Först inskickad
23 maj 2014
Först inskickad som uppfyllde QC-kriterierna
23 maj 2014
Första postat (Uppskatta)
28 maj 2014
Uppdateringar av studier
Senaste uppdatering publicerad (Uppskatta)
12 maj 2016
Senaste inskickade uppdateringen som uppfyllde QC-kriterierna
10 maj 2016
Senast verifierad
1 maj 2016
Mer information
Termer relaterade till denna studie
Ytterligare relevanta MeSH-villkor
Andra studie-ID-nummer
- 03-0505-A
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