• Diabetes
• MASH

• Humans
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/metabolism
• Disease Progression
• Non-alcoholic Fatty Liver Disease/metabolism
• Risk Factors
• Gastrointestinal Microbiome/physiology
• Insulin Resistance/physiology
• Adipose Tissue/metabolism
• Adipose Tissue/pathology

• Elaidic acid
• Gut microbiota
• Linoelaidic acid
• Liver inflammation
• Serum lipidomics

• lipids
• transcription
• gene regulation
• metabolic disorders
• nutrition disorders
• risk factors

• Humans
• Transcription Factors/genetics
• Diabetes Mellitus, Type 2/genetics
• Alleles
• HEK293 Cells
• Fatty Acids/metabolism
• Fatty Acids, Unsaturated
• Fatty Acids, Monounsaturated
• Stearoyl-CoA Desaturase/genetics
• Stearoyl-CoA Desaturase/metabolism
• Proto-Oncogene Protein c-ets-1/genetics

• PD142709 Hungarian National Research, Development and Innovation Office
• K131680 Hungarian National Research, Development and Innovation Office
• FK138115 Hungarian National Research, Development and Innovation Office
• TKP2021-EGA-24 Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund

• AMPK
• Kaempferol
• Lipid accumulation
• NAFLD
• Sirt1

• Mice
• Animals
• Humans
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/metabolism
• Sirtuin 1/metabolism
• AMP-Activated Protein Kinases/metabolism
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/metabolism
• Diabetes Mellitus, Experimental/complications
• Diabetes Mellitus, Experimental/drug therapy
• Diabetes Mellitus, Experimental/metabolism
• Kaempferols/pharmacology
• Kaempferols/therapeutic use
• Liver
• Signal Transduction
• Lipid Metabolism
• Hep G2 Cells
• Lipids/pharmacology
• Mice, Inbred C57BL

• NASH
• cholesterol
• dietary fat
• fatty liver
• saturated fatty acid
• trans fatty acid

• Animals
• Diet, High-Fat/adverse effects
• Dietary Fats/adverse effects
• Disease Models, Animal
• Disease Progression
• Humans
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology

Nonalcoholic steatohepatitis (NASH) is a form of liver disease characterized by steatosis, necroinflammation, and fibrosis, resulting in cirrhosis and cancer. Efforts have focused on reducing the intake of trans fatty acids (TFAs) because of potential hazards to human health and the increased risk for NASH. However, the health benefits of reducing dietary TFAs have not been fully elucidated. Here, the effects of TFAs vs. a substitute on NASH induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet (CDAA-HF) were investigated.

Mice were fed CDAA-HF containing shortening with TFAs (CDAA-HF-T(+)), CDAA-HF containing shortening without TFAs (CDAA-HF-T(−)), or a control chow for 13 or 26 weeks.

At week 13, NASH was induced in mice by feeding CDAA-HF-T(+) containing TFAs or CDAA-HF-T(−) containing no TFAs, but rather mostly saturated fatty acids (FAs), as evidenced by elevated serum transaminase activity and liver changes, including steatosis, inflammation, and fibrosis. CDAA-HF-T(−) induced a greater extent of hepatocellular apoptosis at week 13. At week 26, proliferative (preneoplastic and non-neoplastic) nodular lesions were more pronounced in mice fed CDAA-HF-T(−) than CDAA-HF-T(+).

Replacement of dietary TFAs with a substitute promoted the development of proliferation lesions in the liver of a mouse NASH model, at least under the present conditions. Attention should be paid regarding use of TFA substitutes in foods for human consumption, and a balance of FAs is likely more important than the particular types of FAs.

The online version contains supplementary material available at 10.1186/s12944-020-01423-3.

• Choline-deficient
• High-fat diet
• L-amino acid-defined
• Methionine-lowered
• Nonalcoholic steatohepatitis
• Trans fatty acid substitutes

Even Non-alcoholic steatohepatitis (NASH) has been becoming the key role in process of liver fibrosis or cirrhosis, no any NASH involving liver fibrosis mice model which consistent with the mechanisms of fatty acid and glucose metabolism disorder was widely accepted. Here, we established a mouse model of nonalcoholic steatohepatitis (NASH) with liver fibrosis using a high-fat, high-carbohydrate diet (HFHC) and analyzed the potential pathogenesis using a transcriptome microarray.

Fifty mice were stratified by weight and randomly divided into the HFHC model and control (Con) groups. Ten mice were sacrificed at the beginning of the experiments, 10 mice of HFHC and Con group were euthanized at the end of 20 and 30 weeks. The following analyses were performed: biochemical analysis; histological assessment; evaluation of hepatic type I collagen (Col-I), α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) protein and mRNA expression levels; and transcriptomic gene chip analysis.

Compared with the Con group at each time point, the body weight and liver wet weight of the HFHC model group of mice were significantly higher. At 30th weeks, alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose (FBG) and fasting insulin (FINS) levels or activities and the triglyceride (TG) and hydroxyproline (HYP) content in the HFHC model group were significantly elevated. Severe steatosis was present in the liver tissues contributed from the HFHC group of mice. Typically, substantial perisinusoidal fibrosis with a cage-like structure and bridging formations were observed in the mice liver in HFHC group. Col-I, α-SMA and TGF-β1 protein and mRNA expression levels in liver tissues of HFHC mice dramatically increased over time. Compared with the Con group, the HFHC group had 151 differentially expressed genes that were involved in 41 signaling pathways.

After keeping 30 weeks HFHC diet treatment, the mice exhibited substantial liver fibrosis, hepatic steatosis, ballooning degeneration and inflammation. Basing on the transcriptome microarray assays, the experimental NASH involving liver fibrosis potentially related to dramatically changed ECM-receptor interaction, Toll-like receptor signaling and other signaling pathways.

• Animal model
• Fibrosis
• NASH
• Pathogenesis

• ER stress
• cardiometabolic disease
• cholesterogenesis
• elaidic acid
• industrial trans fatty acid
• inflammation
• lipid metabolism
• ruminant trans fatty acid

• Animals
• Cholesterol
• Dairy Products
• Fatty Acids
• Humans
• Lipid Metabolism
• Trans Fatty Acids/adverse effects

• Voeding, Levensmiddelentechnologie, Agro-Biotechnologie en Gezondheid
• Wageningen University

• Cirrhosis
• Fibroblast growth factor
• Fibroblast growth factor receptor
• Fibrosis
• Hepatocellular carcinoma
• Non-alcoholic fatty liver disease
• Non-alcoholic steatohepatitis

• Carcinoma, Hepatocellular/etiology
• Fibroblast Growth Factors/metabolism
• Humans
• Liver/metabolism
• Liver Neoplasms/etiology
• Non-alcoholic Fatty Liver Disease/complications
• Non-alcoholic Fatty Liver Disease/metabolism
• Receptors, Fibroblast Growth Factor/metabolism
• Signal Transduction

The trans-fat containing AMLN (amylin liver non-alcoholic steatohepatitis, NASH) diet has been extensively validated in C57BL/6J mice with or without the Lep^ob/Lep^ob (ob/ob) mutation in the leptin gene for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH. Due to a recent ban on trans-fats as food additive, there is a marked need for developing a new diet capable of promoting a compatible level of disease in ob/ob and C57BL/6J mice.

To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated fat.

Male ob/ob mice were fed AMLN diet or a modified AMLN diet with trans-fat (Primex shortening) substituted by equivalent amounts of palm oil [Gubra amylin NASH, (GAN) diet] for 8, 12 and 16 wk. C57BL/6J mice were fed the same diets for 28 wk. AMLN and GAN diets had similar caloric content (40% fat kcal), fructose (22%) and cholesterol (2%) level.

The GAN diet was more obesogenic compared to the AMLN diet and impaired glucose tolerance. Biopsy-confirmed steatosis, lobular inflammation, hepatocyte ballooning, fibrotic liver lesions and hepatic transcriptome changes were similar in ob/ob mice fed the GAN or AMLN diet. C57BL/6J mice developed a mild to moderate fibrotic NASH phenotype when fed the same diets.

Substitution of Primex with palm oil promotes a similar phenotype of biopsy-confirmed NASH in ob/ob and C57BL/6J mice, making GAN diet-induced obese mouse models suitable for characterizing novel NASH treatments.

• Non-alcoholic steatohepatitis
• High-fat diet
• Mouse model
• Histopathology
• Fibrosis
• Liver biopsy
• Liver transcriptome

• Animals
• Biopsy
• Diet, High-Fat/adverse effects
• Disease Models, Animal
• Humans
• Leptin/genetics
• Liver/pathology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/pathology
• Palm Oil/adverse effects
• Trans Fatty Acids/adverse effects

• Chrysin
• Fructose
• Hypertension
• Metabolic syndrome
• Triacylglycerol

• Animals
• Diet/methods
• Disease Models, Animal
• Flavonoids/metabolism
• Flavonoids/pharmacology
• Fructose/administration & dosage
• Male
• Metabolic Syndrome/metabolism
• Metabolic Syndrome/prevention & control
• Polyphenols/metabolism
• Polyphenols/pharmacology
• Rats
• Rats, Sprague-Dawley

• 16S rRNA gene sequencing
• Gut microbiota
• Short-chain fatty acid
• Trans-fatty acid

Imbalance in the n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA in the Western diet may increase the risk of nonalcoholic fatty liver disease (NAFLD). This study investigates the impact of substitution of linoleic acid with α-linolenic acid (ALA) or long chain (LC) n-3 PUFA and hence decreasing n-6:n-3 fatty acid ratio on high fat, high fructose (HFHF) diet induced nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were divided into four groups and fed control diet, HFHF diet (n-6:n-3 ratio of 200), HFHF diet with ALA (n-6:n-3 ratio of 2) or HFHF diet with LC n-3 PUFA (n-6:n-3 ratio of 5) for 24 weeks. Rats fed HFHF diet with n-6:n-3 ratio of 200 resulted in hepatic steatosis, induced glucose intolerance, insulin resistance and oxidative stress accompanied by increase in markers of inflammation, plasma lipids and aminotransferase levels. Histopathological examination of liver further confirmed the establishment of NASH. ALA and LC n-3 PUFA supplementation prevented hepatic steatosis and dyslipidemia by inhibiting lipogenesis and increasing insulin sensitivity. Furthermore, n-3 PUFA supplementation attenuated hepatic oxidative stress by restoring antioxidant status, decreased inflammation and preserved hepatic architecture. These finding suggest that decreasing n-6:n-3 ratio prevented HFHF induced NASH by attenuating oxidative stress and inflammation.

The intake of excess dietary fructose most often leads to non-alcoholic fatty liver disease (NAFLD). Fructose is metabolized mainly in the liver and its chronic consumption results in lipogenic gene expression in this organ. However, precisely how fructose is involved in NAFLD progression is still not fully understood, limiting therapy. Lipocalin-2 (LCN2) is a small secreted transport protein that binds to fatty acids, phospholipids, steroids, retinol, and pheromones. LCN2 regulates lipid and energy metabolism in obesity and is upregulated in response to insulin. We previously discovered that LCN2 has a hepatoprotective effect during hepatic insult, and that its upregulation is a marker of liver damage and inflammation. To investigate if LCN2 has impact on the metabolism of fructose and thereby arising liver damage, we fed wild type and Lcn2^−/− mice for 4 or 8 weeks on diets that were enriched in fructose either by adding this sugar to the drinking water (30% w/v), or by feeding a chow containing 60% (w/w) fructose. Body weight and daily intake of food and water of these mice was then measured. Fat content in liver sections was visualized using Oil Red O stain, and expression levels of genes involved in fat and sugar metabolism were measured by qRT-PCR and Western blot analysis. We found that fructose-induced steatosis and liver damage was more prominent in female than in male mice, but that the most severe hepatic damage occurred in female mice lacking LCN2. Unexpectedly, consumption of elevated fructose did not induce de novo lipogenesis or fat accumulation. We conclude that LCN2 acts in a lipid-independent manner to protect the liver against fructose-induced damage.

• NAFLD
• diet
• fat
• fructose
• lipocalin 2
• liver
• steatosis