scholarly journals Machine learning enables new insights into genetic contributions to liver fat accumulation

Cell Genomics ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 100066
Author(s):  
Mary E. Haas ◽  
James P. Pirruccello ◽  
Samuel N. Friedman ◽  
Minxian Wang ◽  
Connor A. Emdin ◽  
...  
Keyword(s):  
Machine Learning ◽  
Liver Fat ◽  
Fat Accumulation ◽  
Genetic Contributions

scholarly journals Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jordi Mayneris-Perxachs ◽  
Marina Cardellini ◽  
Lesley Hoyles ◽  
Jèssica Latorre ◽  
Francesca Davato ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Iron Metabolism ◽  
Gut Microbiome ◽  
Fatty Liver Disease ◽  
Iron Status ◽  
Liver Fat ◽  
Alcoholic Fatty Liver ◽  
Fat Accumulation ◽  
Glycine Transporters ◽  
Alcoholic Fatty Liver Disease

Abstract Background The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear. Results Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The transcriptomic findings were replicated in human primary hepatocytes, where iron supplementation also led to triglycerides accumulation and induced the expression of lipid and iron metabolism genes in synergy with palmitic acid. We further explored the direct impact of the microbiome on iron metabolism and liver fact accumulation through transplantation of faecal microbiota into recipient’s mice. In line with the results in humans, transplantation from ‘high ferritin donors’ resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient’s mice. Conclusions Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies.

scholarly journals Empaglifozin induces changes in the liver metabolome of diabetic rats

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Aragon Herrera ◽  
S Feijoo-Bandin ◽  
M Otero Santiago ◽  
S Moranha Fernandez ◽  
L Anido Varela ◽  
...  
Keyword(s):  
Amino Acids ◽  
Liver Fibrosis ◽  
Diabetic Rats ◽  
Liver Fat ◽  
Favorable Effect ◽  
Funding Source ◽  
Metabolomics Data ◽  
Fat Accumulation ◽  
Glucose Levels ◽  
The Impact

Abstract Background Empagliflozin is a potent, highly selective sodium glucose cotransporter-2 (SGLT2) inhibitor used as an effective and well-tolerated antihyperglycaemic agent. Beyond lowering glucose, empagliflozin exerts a favorable effect on a number of nonglycaemic outcomes, including modest reductions in bodyweight and blood pressure, and it has cardioprotective and renoprotective properties in patients with T2D and established cardiovascular disease (EMPA-REG OUTCOME). Purpose Since liver fat content represents a risk factor for cardiovascular diseases, and empagliflozin has been recently suggested to be able to contribute to the early treatment of nonalcoholic fatty liver disease in T2D, we aimed to study the effect of the empagliflozin treatment in the liver metabolome of type 2 diabetic rats. Methods Male ZDF-Leprfa/fa rats were treated with 30 mg/kg/d of empagliflozin p.o for six weeks. Metabolic profiling of the hepatic tissue was analyzed using UHPLC-MS based platforms. We performed a hematoxylin/eosin staining to determine the tissue integrity and liver fat accumulation, and a Masson's trichrome staining to analyze liver fibrosis. All animals were maintained and euthanized following protocols approved by the Animal Care Committee of the University of Santiago de Compostela in accordance with European Union Directive 2010/63. Results Empaglifozin treatment reduced blood glucose levels to normal (128.2±6.51 mg/dL), while untreated control rats showed high glucose levels (404.3±17.49 mg/dL). Hepatic histological analysis did not show differences regarding neither fat accumulation nor fibrosis between empagliflozin treated and control rats. Circulating levels of cholesterol, HDL, LDL, GTP, GGT triglycerides remained unaltered after empaglifozin treatment vs. control. 384 metabolites were analyzed in the liver tissue samples, observing significantly increased levels of 10 types of glycerolipids, 24 phosphatidylcholines, 8 amino acids, 1 polyunsaturated fatty acid, 4 lysophosphatidylethanolamines, 7 lysophosphatidylinositols, 1 carboxylic acid and 1 nucleoside in the empagliflozin treated rats with respect to the control group. In addition, treatment with empagliflozin produced a significant decrease of 1 glycerolipid, 1 phosphatidylcholine, 1 bile acid, 1 nucleoside and the NAD oxidoreduction coenzyme. Conclusions We demonstrated that empagliflozin significantly modify the liver content of the different lipid species, with the most relevant altered metabolic classes belonging to glycerophospholipids, especially monoacyl-species, and aromatic amino acids. Considering the suggested potential beneficial effect of the treatment with empagliflozin in the prevention of liver fibrosis, our metabolomics data can help to evaluate the impact and the mechanism of action of SGLT2 inhibitors at hepatic level. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim

scholarly journals Effects of Exercise Training on Molecular Markers of Lipogenesis and Lipid Partitioning in Fructose-Induced Liver Fat Accumulation

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Siham Yasari ◽  
Denis Prud'homme ◽  
Frédérique Tesson ◽  
Marek Jankowski ◽  
Jolanta Gutkowska ◽  
...  
Keyword(s):  
Gene Expression ◽  
Exercise Training ◽  
Unsaturated Fatty Acids ◽  
Regulatory Element ◽  
Female Rats ◽  
Liver Fat ◽  
Standard Diet ◽  
Fat Accumulation ◽  
High Fructose ◽  
The Impact

The present study was designed to investigate the impact of exercise training on lipogenic gene expression in liver and lipid partitioning following the ingestion of a high fructose load. Female rats were exercise-trained for 8 wk or kept sedentary before being submitted to a fasting/refeeding protocol. Rats were further subdivided as follow: rats were fasted for 24 h, refed a standard diet for 24 h, starved for another 24 h, and refed with a standard or a high-fructose diet 24 h before sacrifice. Fructose refeeding was associated with an increase in hepatic lipid content, endocannabinoid receptor 1, sterol regulatory element-binding protein1c, and stearoyl-CoA desaturase1 gene expression in both Sed and TR rats. However, desaturation indexes measured in liver (C16 : 1/C16 : 0 and C18 : 1/C18 : 0) and plasma (C18 : 1/C18 : 0) were higher (P<0.01) in TR than in Sed rats following fructose refeeding. It is concluded that exercise training does not significantly affect fat accumulation and the molecular expression of genes involved in lipogenesis after fasting and fructose refeeding but does modify the partitioning of lipids so as to provide more unsaturated fatty acids in liver without affecting liver fat content.

scholarly journals Predicting and elucidating the etiology of fatty liver disease using a machine learning-based approach: an IMI DIRECT study

2020 ◽  
Author(s):  
Naeimeh Atabaki-Pasdar ◽  
Mattias Ohlsson ◽  
Ana Viñuela ◽  
Francesca Frau ◽  
Hugo Pomares-Millan ◽  
...  
Keyword(s):  
Machine Learning ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Prediction Models ◽  
Cell Function ◽  
Area Under The Curve ◽  
Liver Fat ◽  
Irreversible Damage ◽  
Alcoholic Fatty Liver

ABSTRACTBackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in type 2 diabetes (T2D) and beyond. Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and ultimately hepatocellular carcinomas.Methods and FindingsUtilizing the baseline data from the IMI DIRECT participants (n=1514) we sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. Multi-omic (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, and measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI image-derived liver fat content (<5% or ≥5%). We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and Random Forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operator characteristic area under the curve (ROCAUC) of 0.84 (95% confidence interval (CI)=0.82, 0.86), which compared with a ROCAUC of 0.82 (95% CI=0.81, 0.83) for a model including nine clinically-accessible variables. The IMI DIRECT prediction models out-performed existing non-invasive NAFLD prediction tools.ConclusionsWe have developed clinically useful liver fat prediction models (see: www.predictliverfat.org) and identified biological features that appear to affect liver fat accumulation.

Liver fat accumulation is associated with circulating PCSK9

2016 ◽  
Vol 48 (5) ◽  
pp. 384-391 ◽  
Author(s):  
Massimiliano Ruscica ◽  
Nicola Ferri ◽  
Chiara Macchi ◽  
Marica Meroni ◽  
Claudia Lanti ◽  
...  
Keyword(s):  
Liver Fat ◽  
Fat Accumulation

scholarly journals Pregnancy facilitates maternal liver regeneration after partial hepatectomy

2020 ◽  
Vol 318 (4) ◽  
pp. G772-G780
Author(s):  
Joonyong Lee ◽  
Veronica Garcia ◽  
Shashank Manohar Nambiar ◽  
Huaizhou Jiang ◽  
Guoli Dai
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Liver Resection ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Liver Fat ◽  
Fat Accumulation ◽  
Positive Effects ◽  
Maternal Liver ◽  
Hepatic Fat

Liver resection induces robust liver regrowth or regeneration to compensate for the lost tissue mass. In a clinical setting, pregnant women may need liver resection without terminating pregnancy in some cases. However, how pregnancy affects maternal liver regeneration remains elusive. We performed 70% partial hepatectomy (PH) in nonpregnant mice and gestation day 14 mice, and histologically and molecularly compared their liver regrowth during the next 4 days. We found that compared with the nonpregnant state, pregnancy altered the molecular programs driving hepatocyte replication, indicated by enhanced activities of epidermal growth factor receptor and STAT5A, reduced activities of cMet and p70S6K, decreased production of IL-6, TNFα, and hepatocyte growth factor, suppressed cyclin D1 expression, increased cyclin A1 expression, and early activated cyclin A2 expression. As a result, pregnancy allowed the remnant hepatocytes to enter the cell cycle at least 12 h earlier, increased hepatic fat accumulation, and enhanced hepatocyte mitosis. Consequently, pregnancy ameliorated maternal liver regeneration following PH. In addition, a report showed that maternal liver regrowth after PH is driven mainly by hepatocyte hypertrophy rather than hyperplasia during the second half of gestation in young adult mice. In contrast, we demonstrate that maternal liver relies mainly on hepatocyte hyperplasia instead of hypertrophy to restore the lost mass after PH. Overall, we demonstrate that pregnancy facilitates maternal liver regeneration likely via triggering an early onset of hepatocyte replication, accumulating excessive liver fat, and promoting hepatocyte mitosis. The results from our current studies enable us to gain more insights into how maternal liver regeneration progresses during gestation. NEW & NOTEWORTHY We demonstrate that pregnancy may generate positive effects on maternal liver regeneration following partial hepatectomy, which are manifested by early entry of the cell cycle of remnant hepatocytes, increased hepatic fat accumulation, enhanced hepatocyte mitosis, and overall accelerated liver regrowth.

scholarly journals Sphingosine 1-Phosphate Receptor Blockade Affects Pro-Inflammatory Bone Marrow-Derived Macrophages and Relieves Mouse Fatty Liver Injury

2019 ◽  
Vol 20 (19) ◽  
pp. 4695 ◽  
Author(s):  
Jingjing Yang ◽  
Na Chang ◽  
Le Yang ◽  
Xiaofang Ji ◽  
Xuan Zhou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Liver Injury ◽  
Fatty Liver ◽  
Pathological Process ◽  
Liver Fat ◽  
Inflammatory Factor ◽  
Gene Expressions ◽  
Fat Accumulation ◽  
Sphingosine 1 Phosphate

Fatty liver injury is characterized by liver fat accumulation and results in serious health problems worldwide. There is no effective treatment that reverses fatty liver injury besides etiological therapy. Inflammation is an important macrophage-involving pathological process of liver injury. Here, we investigated the role of sphingosine 1-phosphate receptors (S1PRs) in fatty liver injury and explored whether S1PR2/3 blockade could cure fatty liver injury. A methionine-choline-deficient and a high-fat (MCDHF) diet was used to induce fatty liver injury, and the number of macrophages was evaluated by flow cytometry. Gene expressions were detected using RT-qPCR and cytometric bead array. In MCDHF-diet-fed mice, pro-inflammatory factor expressions were upregulated by fatty liver injury. The S1P level and S1PR2/3 expressions were significantly elevated. Moreover, increased S1P level and S1PR2/3 mRNA expressions were positively correlated with pro-inflammatory factor expressions in the liver. Furthermore, the number of pro-inflammatory macrophages (iMφ) increased in injured liver, and they were mainly bone-marrow-derived macrophages. In vivo, S1PR2/3 blockade decreased the amount of iMφ and inflammation and attenuated liver injury and fibrosis, although liver fat accumulation was unchanged. These data strongly suggest that anti-inflammatory treatment by blocking the S1P/S1PR2/3 axis attenuates fatty liver injury, which might serve as a potential target for fatty liver injury.

scholarly journals Camellia oleifera seed extract attenuated abdominal and hepatic fat accumulation in rats fed a high-fat diet

2019 ◽  
Vol 44 (3) ◽  
pp. 320-325 ◽  
Author(s):  
Hsin-Yi Yang ◽  
Wan-Ju Yeh ◽  
Jung Ko ◽  
Jiun-Rong Chen
Keyword(s):  
High Fat Diet ◽  
Control Diet ◽  
Water Extract ◽  
Liquid Diet ◽  
Hot Water ◽  
Liver Fat ◽  
Camellia Oleifera ◽  
High Fat ◽  
Fat Accumulation ◽  
Hepatic Fat

The objective of this study was to evaluate the effects of the hot-water extract of defatted Camellia oleifera seeds (CSE) on body and liver fat accumulation in rats. Forty rats were divided into 5 groups and each group was fed either an isocaloric control diet or a high-fat liquid diet with 0% (H), 0.12% (H1), 0.24% (H2), or 0.48% CSE (H3) for 8 weeks. Ingestion of the high-fat liquid diet increased abdominal and liver fat accumulation, although no difference was found in body weights compared with rats fed the control diet. We found that rats fed the H2 and H3 diets had lower plasma alanine aminotransferase activities than the H group in the fourth and eighth weeks. At the end of the study, the H2 and H3 groups also had lower epididymal and retroperitoneal fat masses, and all CSE groups had lower circulatory leptin levels than the H group. CSE consumption decreased hepatic fat accumulation in terms of liver triglycerides and a histopathology analysis, and ameliorated high-fat diet-induced elevation of hepatic tumor necrosis factor-α levels. We also found that CSE groups had lower malondialdehyde and hydroxyproline levels in the liver. Our results suggested that CSE may exert beneficial effects through decreasing body fat accumulation and hepatic steatosis and regulating adipokine levels in diet-induced nonalcoholic fatty liver disease.

scholarly journals Abdominal Fat and Metabolic Health Markers but Not PNPLA3 Genotype Predicts Liver Fat Accumulation in Response to Excess Intake of Energy and Saturated Fat in Healthy Individuals

2020 ◽  
Vol 7 ◽  
Author(s):  
Fredrik Rosqvist ◽  
Marju Orho-Melander ◽  
Joel Kullberg ◽  
David Iggman ◽  
Hans-Erik Johansson ◽  
...  
Keyword(s):  
Energy Intake ◽  
Saturated Fat ◽  
Liver Fat ◽  
Double Blind ◽  
Fat Accumulation ◽  
Healthy Men ◽  
Metabolically Healthy ◽  
Metabolic Variables ◽  
Glutamyl Transferase ◽  
Hypercaloric Diet

Background: Saturated fat (SFA) has consistently been shown to increase liver fat, but the response appears variable at the individual level. Phenotypic and genotypic characteristics have been demonstrated to modify the hypercholesterolemic effect of SFA but it is unclear which characteristics that predict liver fat accumulation in response to a hypercaloric diet high in SFA.Objective: To identify predictors of liver fat accumulation in response to an increased intake of SFA.Design: We pooled our two previously conducted double-blind randomized trials (LIPOGAIN and LIPOGAIN-2, clinicaltrials.gov NCT01427140 and NCT02211612) and used data from the n = 49 metabolically healthy men (n = 32) and women (n = 17) randomized to a hypercaloric diet through addition of SFA-rich muffins for 7–8 weeks. Associations between clinical and metabolic variables at baseline and changes in liver fat during the intervention were analyzed using Spearman rank correlation. Linear regression was used to generate a prediction model.Results: Liver fat increased by 33% (IQR 5.4–82.7%; P &lt; 0.0001) in response to excess energy intake and this was not associated (r = 0.17, P = 0.23) with the increase in body weight (1.9 kg; IQR 1.1–2.9 kg). Liver fat accumulation was similar (P = 0.28) in carriers (33%, IQR 14–79%) and non-carriers (33%, IQR −11 to +87%) of the PNPLA3-I148M variant. Baseline visceral and liver fat content, as well as levels of the liver enzyme γ-glutamyl transferase (GT), were the strongest positive predictors of liver fat accumulation—in contrast, adiponectin and the fatty acid 17:0 in adipose tissue were the only negative predictors in univariate analyses. A regression model based on eight clinical and metabolic variables could explain 81% of the variation in liver fat accumulation.Conclusion: Our results suggest there exists a highly inter-individual variation in the accumulation of liver fat in metabolically healthy men and women, in response to an increased energy intake from SFA and carbohydrates that occurs over circa 2 months. This marked variability in liver fat accumulation could largely be predicted by a set of clinical (e.g., GT and BMI) and metabolic (e.g., fatty acids, HOMA-IR, and adiponectin) variables assessed at baseline.

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