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Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition.

ABSTRACT: BACKGROUND: There are only few data relating the metabolic consequences of feeding diets very low in n-3 fatty acids. This experiment carried out in mice aims at studying the impact of dietary n-3 polyunsaturated fatty acids (PUFA) depletion on hepatic metabolism. RESULTS: n-3 PUFA depletion leads to a significant decrease in body weight despite a similar caloric intake or adipose tissue weight. n-3 PUFA depleted mice exhibit hypercholesterolemia (total, HDL, and LDL cholesterol) as well as an increase in hepatic cholesteryl ester and triglycerides content. Fatty acid pattern is profoundly modified in hepatic phospholipids and triglycerides. The decrease in tissue n-3/n-6 PUFA ratio correlates with steatosis. Hepatic mRNA content of key factors involved in lipid metabolism suggest a decreased lipogenesis (SREBP-1c, FAS, PPAR gamma), and an increased beta-oxidation (CPT1, PPAR alpha and PGC1 alpha) without modification of fatty acid esterification (DGAT2, GPAT1), secretion (MTTP) or intracellular transport (L-FABP). Histological analysis reveals alterations of liver morphology, which can not be explained by inflammatory or oxidative stress. However, several proteins involved in the unfolded protein response are decreased in depleted mice. CONCLUSION: n-3 PUFA depletion leads to important metabolic alterations in murine liver. Steatosis occurs through a mechanism independent of the shift between beta-oxidation and lipogenesis. Moreover, long term n-3 PUFA depletion decreases the expression of factors involved in the unfolded protein response, suggesting a lower protection against endoplasmic reticulum stress in hepatocytes upon n-3 PUFA deficiency.

SUBMITTER: Pachikian BD

PROVIDER: S-EPMC2612019 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition.

Pachikian B D BD Neyrinck A M AM Cani P D PD Portois L L Deldicque L L De Backer F C FC Bindels L B LB Sohet F M FM Malaisse W J WJ Francaux M M Carpentier Y A YA Delzenne N M NM

BMC physiology 20081201

<h4>Background</h4>There are only few data relating the metabolic consequences of feeding diets very low in n-3 fatty acids. This experiment carried out in mice aims at studying the impact of dietary n-3 polyunsaturated fatty acids (PUFA) depletion on hepatic metabolism.<h4>Results</h4>n-3 PUFA depletion leads to a significant decrease in body weight despite a similar caloric intake or adipose tissue weight. n-3 PUFA depleted mice exhibit hypercholesterolemia (total, HDL, and LDL cholesterol) as ...[more]

PMID: 19046413

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Project description:BackgroundIn patients with metabolic-associated fatty liver disease (MAFLD), hepatic steatosis is the first step of diagnosis, and it is a risk predictor that independently predicts insulin resistance, cardiovascular risk, and mortality. Urine biomarkers have the advantage of being less complex, with a lower dynamic range and fewer technical challenges, in comparison to blood biomarkers.MethodsHepatic steatosis was measured by magnetic resonance imaging (MRI), which measured the proton density fat fraction (MRI-PDFF). Mild hepatic steatosis was defined as MRI-PDFF 5-10% and severe hepatic steatosis was defined as MRI-PDFF > 10%.ResultsMAFLD patients with any kidney diseases were excluded. There were 53 proteins identified by mass spectrometry with significantly different expressions among the healthy control, mild steatosis, and severe steatosis patients. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of these significantly changed urinary molecular features correlated with the liver, resulting in the dysregulation of carbohydrate derivative/catabolic/glycosaminoglycan/metabolic processes, insulin-like growth factor receptor levels, inflammatory responses, the PI3K-Akt signaling pathway, and cholesterol metabolism. Urine alpha-1-acid glycoprotein 1 (ORM1) and ceruloplasmin showed the most significant correlation with the clinical parameters of MAFLD status, including liver fat content, fibrosis, ALT, triglycerides, glucose, HOMA-IR, and C-reactive protein. According to ELISA and western blot (30 urine samples, normalized to urine creatinine), ceruloplasmin (ROC 0.78, p = 0.034) and ORM1 (ROC 0.87, p = 0.005) showed moderate diagnostic accuracy in distinguishing mild steatosis from healthy controls. Ceruloplasmin (ROC 0.79, p = 0.028) and ORM1 (ROC 0.81, p = 0.019) also showed moderate diagnostic accuracy in distinguishing severe steatosis from mild steatosis.ConclusionsCeruloplasmin and ORM1 are potential biomarkers in distinguishing mild and severe steatosis in MAFLD patients.

Project description:in the present study, we evaluated whether microbiota modulation is able to restore hepatic steatosis induced by n-3 PUFA depletion in mice. For this purpose, mice were fed during three months with a n-3 PUFA-depleted diet (presenting a high n-6/n-3 PUFA ratio), and then supplemented with fructooligosaccharides (FOS, 0.25g/day/mice), a prebiotic, during the last ten days of the experiment (DEF/FOS). In the same time, some n-3 PUFA-depleted mice were returned on a control diet during the last 10 days of treatment (DEF/CT) to compare the effect of FOS supplementation to a restored intake in n-3 PUFA. Microarray analyses were performed to identify the molecular targets modified by FOS supplementation in the liver of n-3 PUFA depleted mice. These mice were compared to control mice (fed a control diet during the 112 days of experiment) and to n-3 PUFA-depleted mice (fed a n-3 PUFA-depleted diet during the 112 days of experiment) for which the results have been previously published (Pachikian B.D. et al. PLoS One. 2011;6(8):e23365, accession number GSE26986) Male C57Bl/6J mice (9 weeks old; Charles River, Brussels, Belgium) were housed in groups of 4 mice per cage at 22Â°C in a 12 h light/dark cycle and given free access to diet and water. After an acclimatisation period of 1 week, mice were fed a control (CT) (D08041805, Research Diets, New Brunswick, USA) or an n-3 PUFA-depleted diet (DEF) (D08041806, Research Diets, New Brunswick, USA) for 112 days ad libitum. The CT diet contained the following (percent w/w): casein 20, total carbohydrate 72.4 (including corn starch 44.2, sucrose 10, maltodextrin 13.2, cellulose 5), soybean oil 5, mineral mix 3.5 and vitamin mix 1. The depletion was induced by replacing the soybean oil with sunflower oil, which exhibited a higher n-6/n-3 PUFA ratio. The n-6/n-3 PUFA ratio was 6.9 and 127.2 for the CT diet and the DEF diet, respectively. Ten days before the end of the experiment, DEF mice were divided into three groups: DEF, DEF/FOS and DEF/CT mice. The DEF mice were still fed with the n-3 PUFA depleted diet (DEF). The DEF/FOS mice were still fed the DEF diet and were supplemented for 10 days with fructooligosaccharides (DEF/FOS). FOS (Beneo P95 gift from Orafti; Tienen, Belgium) was added to tap water in a concentration adequate to reach an intake of 0.25g of FOS per day. For DEF/CT mice, the DEF diet was replaced by the CT diet during the last 10 days of treatment. At the end of the study period, mice fed the CT (n=4), DEF (n=7), DEF/CT (n=8) or DEF/FOS diet (n=8) were anaesthetised (ketamine/xylazine i.p., 100 and 10 mg/kg of body weight, respectively). The liver tissue was immediately clamped in liquid N2 and kept at -80Â°C until analysis. All mice experiments were approved by the local animal ethics committee and the housing conditions were as specified by the Belgian Law of April 6, 2010 on the protection of laboratory animals (agreement nÂ° LA 1230314).

Dataset Information

Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition.

Publications

Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition.

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