A Diet-Induced Pediatric Model of Non Alcoholic Fatty Liver Disease Using Neonatal Iberian Pigs (OR26-02-19)

Abstract Objectives The prevalence of non-alcoholic fatty liver disease (NAFLD) in children has increased over the past decades, creating a need for animal models that recapitulate the features of the pediatric disease. Iberian pigs have a leptin-resistant phenotype characterized by hyperleptinemia, hyperphagia, and extreme adipogenesis. We hypothesized that neonatal Iberian pigs fed a high-fat high-fructose (HFF) diet will develop a pattern of liver injury resembling pediatric NAFLD. In addition, we sought to determine if a mixture of probiotics would prevent the disease. Methods Animals were fed 1 of 4 diets containing (g/kg body weight × d) 0 g fructose, 11 g fat and 199 kcal (CON-N; n = 8), 22 g fructose, 16 g fat and 300 kcal (HFF-N; n = 6), CON + probiotic (CON-P; n = 6), or HFF + probiotic (HFF-P; n = 6) every 6 h for 70 d. The probiotic mixture (6.2 × 104cfu/mL) contained Pediococcus, Lactobacillus and Bacillus. Body weight was recorded every 3 d. Serum markers of liver injury and dyslipidemia were measured on d 65 at 2 h post feeding. Fasting leptin, insulin, glucose and homeostatic model assessment (HOMA) values were assessed on d 70. Liver tissue was collected on d 70 for histology, triacylglyceride (TG) quantification, and gene expression of tumor necrosis factor (TNF) α, tumor growth factor (TGF) β, interleukin (IL) 1α, peroxisome proliferator-activated receptor (PPAR) γ, carbohydrate-responsive element-binding protein (ChREBP) and sterol regulatory element-binding protein (SREBP) 1c. Results Body weight was higher in CON-P, and insulin and HOMA values in HFF-P and CON-P (P ≤ 0.05). Leptin, alanine and aspartate aminotransferases, alkaline phosphatase, lactate dehydrogenase and total bilirubin were increased (P ≤ 0.001), and high and low density lipoproteins decreased (P ≤ 0.05) in HFF-N and HFF-P. Livers in HFF-P and HFF-N had higher relative weight and TG (P ≤ 0.001), micro and macrovesicular steatosis, ballooning degeneration, Mallory-denk bodies, inflammation and necrosis, increased gene expression of TNFα, TGFβ, IL1α and PPARγ (P ≤ 0.001), and decreased ChREBP (P ≤ 0.001). Conclusions Iberian pigs fed a HFF diet recapitulate many pediatric NAFLD-associated features, in the absence of obesity and independently of probiotic supplementation, suggesting a potentially suitable model for pediatric NAFLD research. Funding Sources ARI, AcornSeekers.

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Molecular pathways involved in the improvement of non-alcoholic fatty liver disease

Journal of Molecular Endocrinology ◽

10.1530/jme-13-0072 ◽

2013 ◽

Vol 51 (1) ◽

pp. 167-179 ◽

Cited By ~ 11

Author(s):

Gilberto Paz-Filho ◽

Claudio Alberto Mastronardi ◽

Brian J Parker ◽

Ainy Khan ◽

Antonio Inserra ◽

...

Keyword(s):

Body Weight ◽

Liver Disease ◽

Liver Injury ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Glutathione Metabolism ◽

Wild Type ◽

Alcoholic Fatty Liver ◽

The Metabolic Syndrome ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis are components of the metabolic syndrome. Serum leptin levels are elevated in obesity, but the role of leptin in the pathophysiology of the liver involvement is still unclear. To identify the effects and mechanisms by which leptin influences the pathogenesis of NAFLD, we performed epididymal white adipose tissue (eWAT) transplantation from congenic wild-type mice into the subcutaneous dorsal area ofLepob/obrecipient mice and compared the results with those of theLepob/obsham-operated mice. The mice were followed for 102–216 days. During killing, the transplanted mice had significantly lost body weight and exhibited significantly higher leptin levels, improved glucose tolerance, and lower liver injury scores than the sham-operated mice. Liver microarray analysis showed that novel pathways related to GA-binding protein (GABP) transcription factor targets, pheromone binding, and olfactory signaling were differentially expressed in the transplanted mice. Our data also replicate pathways known to be involved in NAFLD, such as those involved in the regulation of microRNAs, lipid, glucose, and glutathione metabolism, peroxisome proliferator-activated receptor signaling, cellular regulation, carboxylic acid processes, iron, heme, and tetrapyrrole binding, immunity and inflammation, insulin signaling, cytochrome P450 function, and cancer. Conclusion: wild-type eWAT transplantation intoLepob/obmice led to improvements in metabolism, body weight, and liver injury, possibly attributed to the production of leptin by the transplanted eWAT. These improvements were accompanied by the differential expression of novel pathways. The causal relationship between GABP downregulation and NAFLD improvement remains to be determined.

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The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms222111383 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11383

Author(s):

Geng-Ruei Chang ◽

Wei-Li Lin ◽

Tzu-Chun Lin ◽

Huei-Jyuan Liao ◽

Yu-Wen Lu

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Binding Protein ◽

Health Concern ◽

Fibroblast Growth Factor 21 ◽

Alcoholic Fatty Liver ◽

Underlying Mechanisms ◽

Alcoholic Fatty Liver Disease

Liver disorders are a major health concern. Saikosaponin-d (SSd) is an effective active ingredient extracted from Bupleurum falcatum, a traditional Chinese medicinal plant, with anti-inflammatory and antioxidant properties. However, its hepatoprotective properties and underlying mechanisms are unknown. We investigated the effects and underlying mechanisms of SSd treatment for thioacetamide (TAA)-induced liver injury and high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in male C57BL/6 mice. The SSd group showed significantly higher food intake, body weight, and hepatic antioxidative enzymes (catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) and lower hepatic cyclooxygenase-2 (COX-2), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and fibroblast growth factor-21 (FGF21) compared with controls, as well as reduced expression of inflammation-related genes (nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS)) messenger RNA (mRNA). In NAFLD mice, SSd reduced serum ALT, AST, triglycerides, fatty acid–binding protein 4 (FABP4) and sterol regulatory element–binding protein 1 (SREBP1) mRNA, and endoplasmic reticulum (ER)-stress-related proteins (phosphorylated eukaryotic initiation factor 2α subunit (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). SSd has a hepatoprotective effect in liver injury by suppressing inflammatory responses and acting as an antioxidant.

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Healthy PNPLA3 Risk Allele Carriers Present with Unexpected Body Fat Composition. A Study of One ousand Subjects

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld-1276 ◽

2014 ◽

Vol 23 (1) ◽

pp. 33-37 ◽

Cited By ~ 2

Author(s):

Agnieszka Kempinska-Podhorodecka ◽

Marcin Krawczyk ◽

Marta Klak ◽

Malgorzata Blatkiewicz ◽

Frank Lammert ◽

...

Keyword(s):

Body Weight ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

The Metabolic Syndrome ◽

Anthropometric Characteristics ◽

The Common ◽

Total Fat ◽

Alcoholic Fatty Liver Disease

Introduction: The common PNPLA3 (adiponutrin) variant p.I148M represents a major genetic driver of progression in non-alcoholic fatty liver disease (NAFLD). NAFLD is commonly associated with traits of the metabolic syndrome, therefore it is mostly suspected in obese individuals. Here, we investigate the association between the PNPLA3 variant and anthropometric traits in a cohort of healthy individuals.Patients and methods: We recruited 1,000 (500 females; age 18 - 66 years) healthy blood donors. The PNPLA3 variant was genotyped using TaqMan assays. All individuals were phenotyped with respect to anthropometric characteristics. We also determined the percentage of total fat (F%) and active tissue (TA%) of body weight.Results: Healthy carriers of the PNPLA3 [IM] and [MM] genotypes, although not differing in height from individuals with the genotype [II], displayed significantly lower body weight and lower BMI (both P = 0.005), higher TA% (P = 0.03) but lower F% (P = 0.03) and smaller waist, chest and shin circumferences (all P < 0.05). Separate analysis for males and females demonstrated an association between the [IM] and [MM] genotypes and higher TA% but lower F% (P = 0.04) in females. In males, BMI and total weight were significantly (P = 0.04) lower among carriers of the [M] allele.Discussion: Healthy individuals carrying the prosteatotic PNPLA3 allele p.I48M may be leaner as compared to the carriers of the common allele. Hence in clinical practice they might be overlooked since they do not necessarily present with the anthropometric characteristics commonly associated with severe hepatic steatosis.Abbreviations: ATX - autotaxin; BMI - body mass index; F% - total fat of body weight in %; Fkg - total fat of body weight in kilograms; GWAS - genome-wide association study; LPA - lysophosphatidic acid; NAFLD, non-alcoholic fatty liver disease; NASH - non-alcoholic steatohepatitis; PA - phosphatidic acid; PNPLA3-patatin-like phospholipase domain containing 3 (adiponutrin); TA% - active tissue of body weight in %; TAkg - active tissue of body weight in kilograms; WHR - waist-to-hip ratio.

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Histone modifications in fatty acid synthase modulated by carbohydrate responsive element binding protein are associated with non‑alcoholic fatty liver disease

International Journal of Molecular Medicine ◽

10.3892/ijmm.2018.3702 ◽

2018 ◽

Cited By ~ 2

Author(s):

Can Cai ◽

Huihong Yu ◽

Guangming Huang ◽

Xuan Du ◽

Xiaoqing Yu ◽

...

Keyword(s):

Fatty Acid ◽

Liver Disease ◽

Fatty Liver ◽

Histone Modifications ◽

Fatty Liver Disease ◽

Fatty Acid Synthase ◽

Alcoholic Fatty Liver ◽

Element Binding Protein ◽

Responsive Element ◽

Alcoholic Fatty Liver Disease

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Evaluation of potential gene expression as early markers of insulin resistance and non-alcoholic fatty liver disease in the Indonesian population

Indonesian Journal of Biotechnology ◽

10.22146/ijbiotech.36975 ◽

2018 ◽

Vol 23 (2) ◽

pp. 84

Author(s):

Eunice Limantara ◽

Felicia Kartawidjajaputra ◽

Antonius Suwanto

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Model Assessment ◽

Gene Expressions ◽

Alcoholic Fatty Liver ◽

Early Markers ◽

Alcoholic Fatty Liver Disease

Early detection of insulin resistance (IR) or non-alcoholic fatty liver disease (NAFLD) is crucial to preventing future risks of developing chronic diseases. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Liver Fat Score (LFS), and Fatty Liver Index (FLI) are generally employed to measure severity stages of IR and NAFLD. The study of gene expressions could explain the molecular mechanisms that occur early on in IR and NAFLD; thus providing potential early markers for both diseases. This study was conducted to evaluate the gene expressions that could potentially be early markers of IR and NAFLD. All participants (n = 21) had normal blood glucose and were categorized as without hepatosteatosis (n = 10), at higher risk of hepatosteatosis (n = 6), and hepatosteatosis (n = 5). Gene expression analysis was performed using the 2-∆∆CT relative quantification method. There were significant differences in galnt2 (p < 0.002) and sirt1 (p < 0.010) expression between the first and the third tertiles of HOMA-IR; and in ptpn1 (p < 0.012) expression between the first and the second tertiles of LFS. In conclusion, the expressions of galnt2 and sirt1 could be used as early markers of IR, while the expression of ptpn1 could be employed as an early marker of NAFLD.

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