scholarly journals AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease

Metabolism ◽  
2019 ◽  
Vol 99 ◽  
pp. 67-80 ◽  
Author(s):  
Nikolaos Nikolaou ◽  
Laura L. Gathercole ◽  
Lea Marchand ◽  
Sara Althari ◽  
Niall J. Dempster ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Human Hepatocytes ◽  
Metabolic Phenotype ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

scholarly journals Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

2021 ◽  
Author(s):  
Mohammad Kabbani ◽  
Eleftherios Michailidis ◽  
Sandra Steensels ◽  
Clifton Fulmer ◽  
Joseph Luna ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Human Genetics ◽  
Human Hepatocytes ◽  
Chimeric Mice ◽  
Human Donor ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease ◽  
Global Health Problem

Abstract Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of chimeric mice respond to hypercaloric diets. As early as 4 weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatohepatitis selectively in the human graft, followed by pericellular fibrosis after 8 weeks of hypercaloric feeding. The PNPLA3 148M variant, either from a homozygous 148M human donor or overexpressed in a homozygous 148I donor background, caused microvesicular and more severe steatosis. In these livers hepatocytes displayed frequent ballooning degeneration, resulting in more active steatohepatitis than in 148I livers. We conclude that PNPLA3 148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetics associated with advanced fatty liver diseases.

scholarly journals Metabolomic Characterization of a Novel Pig Model of Pediatric Non-alcoholic Fatty Liver Disease (P08-131-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Michael La Frano ◽  
Gabriella Hernandez ◽  
Victoria Smith ◽  
Dan Columbus ◽  
Daniel Peterson ◽  
...  
Keyword(s):  
Liver Disease ◽  
Carbon Cycle ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Low Density Lipoproteins ◽  
Pig Model ◽  
Metabolic Phenotype ◽  
Low Density ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Abstract Objectives Non-alcoholic fatty liver disease (NAFLD) is a leading nutrition-linked liver disease in children. We have recently identified the neonatal Iberian pig as a novel model of pediatric NAFLD. Interestingly, feeding a high fructose-high fat (HFF) diet to neonatal Iberian pigs for 10 weeks did not induce obesity and decreased high and low density lipoproteins in serum, while the liver exhibited many of the histological features of pediatric NAFLD. In this study we utilized a metabolomics approach to characterize the metabolic phenotype of this pig model. Methods Plasma and liver samples collected from Iberian pigs fed control, HFF, control + probiotic and HFF + probiotic diets were analyzed by LC-MS using targeted assays for primary metabolomics, aminomics, and lipidomics. Data was analyzed with multivariate statistics and 2-way ANOVA with t-tests adjusted for false discovery rate. Results Results from multivariate tests indicated no diet × probiotic interaction or probiotic effect, so only the main effect of diet is shown. A total of 224 and 218 metabolites were identified in the plasma and liver, respectively. In agreement with previous NAFLD models, the HFF diet increased hepatic branched chain amino acids, cholesteryl esters, hydroxyproline, plasma acylcarnitines and primary bile acids, and altered hepatic triacylglycerol-species composition (P < 0.0001). In addition, HFF pigs had increased homocysteine and methionine levels combined with a decrease in pyridoxate in liver (P < 0.0001), suggesting a disruption in the one carbon cycle and its methyl donation capability. HFF decreased hepatic choline and betaine (P < 0.0001), which may indicate a compensatory use of the methyl groups of these compounds. The aforementioned reduction of choline used for the CDP-choline pathway and the potential one carbon cycle impact on SAM availability for the phosphatidylethanolamine N-methyltransferase (PEMT) pathway may explain the observed differential changes in hepatic phosphatidylcholines (P < 0.0001), which are required for the production of very low density lipoproteins (VLDL). Conclusions Unique features of this model such as reduced plasma lipoproteins and lack of weight gain in the presence of hepatic steatosis may be related to an altered one carbon cycle impacting phosphatidylcholine production. Funding Sources ARI, AcornSeekers.

scholarly journals The Contribution of Dietary Fructose to Non-alcoholic Fatty Liver Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Siyu Yu ◽  
Chunlin Li ◽  
Guang Ji ◽  
Li Zhang
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
De Novo ◽  
Close Association ◽  
Metabolic Phenotype ◽  
Alcoholic Fatty Liver ◽  
Fructose Metabolism ◽  
Dietary Fructose ◽  
Alcoholic Fatty Liver Disease

Fructose, especially industrial fructose (sucrose and high fructose corn syrup) is commonly used in all kinds of beverages and processed foods. Liver is the primary organ for fructose metabolism, recent studies suggest that excessive fructose intake is a driving force in non-alcoholic fatty liver disease (NAFLD). Dietary fructose metabolism begins at the intestine, along with its metabolites, may influence gut barrier and microbiota community, and contribute to increased nutrient absorption and lipogenic substrates overflow to the liver. Overwhelming fructose and the gut microbiota-derived fructose metabolites (e.g., acetate, butyric acid, butyrate and propionate) trigger the de novo lipogenesis in the liver, and result in lipid accumulation and hepatic steatosis. Fructose also reprograms the metabolic phenotype of liver cells (hepatocytes, macrophages, NK cells, etc.), and induces the occurrence of inflammation in the liver. Besides, there is endogenous fructose production that expands the fructose pool. Considering the close association of fructose metabolism and NAFLD, the drug development that focuses on blocking the absorption and metabolism of fructose might be promising strategies for NAFLD. Here we provide a systematic discussion of the underlying mechanisms of dietary fructose in contributing to the development and progression of NAFLD, and suggest the possible targets to prevent the pathogenetic process.

Vitamin D levels are not associated with non-alcoholic fatty liver disease severity in a Brazilian population

2020 ◽  
pp. 1-8
Author(s):  
Jeniffer Danielle M. Dutra ◽  
Quelson Coelho Lisboa ◽  
Silvia Marinho Ferolla ◽  
Carolina Martinelli M. L. Carvalho ◽  
Camila Costa M. Mendes ◽  
...  
Keyword(s):  
Vitamin D ◽  
Liver Disease ◽  
Fatty Liver ◽  
Disease Severity ◽  
Fatty Liver Disease ◽  
Hypovitaminosis D ◽  
Alcoholic Fatty Liver ◽  
Vitamin D Levels ◽  
The Mean ◽  
Alcoholic Fatty Liver Disease

Abstract. Some epidemiological evidence suggests an inverse correlation between non-alcoholic fatty liver disease (NAFLD) frequency and vitamin D levels. Likewise, a beneficial effect of vitamin D on diabetes mellitus (DM) and insulin resistance has been observed, but this is an unsolved issue. Thus, we aimed to investigate the prevalence of hypovitaminosis D in a NAFLD Brazilian population and its association with disease severity and presence of comorbidities. In a cross-sectional study, the clinical, biochemical and histological parameters of 139 NAFLD patients were evaluated according to two different cut-off points of serum 25-hydroxyvitamin D levels (20 ng/mL and 30 ng/mL). The mean age of the population was 56 ± 16 years, most patients were female (83%), 72% had hypertension, 88% dyslipidemia, 46% DM, 98% central obesity, and 82% metabolic syndrome. Serum vitamin D levels were < 30 ng/mL in 78% of the patients, and < 20 ng/mL in 35%. The mean vitamin D level was 24.3 ± 6.8 ng/mL. The comparison between the clinical, biochemical and histological characteristics of the patients according to the levels of vitamin D showed no significant difference. Most patients with NAFLD had hypovitaminosis D, but low vitamin D levels were not related to disease severity and the presence of comorbidities.

Non-Alcoholic Fatty Liver Disease in Overweight Children and its Relationship with Retinol Serum Levels

2008 ◽  
Vol 78 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Suano de Souza ◽  
Silverio Amancio ◽  
Saccardo Sarni ◽  
Sacchi Pitta ◽  
Fernandes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Lipid Profile ◽  
Fatty Liver Disease ◽  
Thiobarbituric Acid ◽  
Serum Levels ◽  
Control Group ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Objectives: To evaluate the frequency of non-alcoholic fatty liver disease, the retinol serum levels, lipid profile, and insulin resistance in overweight/obese children. To relate these biochemical variables with the risk of this disease in the population studied. Methods: The study was cross-sectional and prospective, with 46 overweight/obese school children (28 female, 18 male; mean age 8.6 years). The control group consisted of 45 children, paired by age and gender. Hepatic steatosis, evaluated by ultrasound, was classified as normal, mild, moderate, or severe. Also evaluated were serum retinol levels; thiobarbituric acid reactive substances; lipid profile; and fasting glucose and serum insulin levels, used for the calculation of the Homeostasis Model Assessment. Results: Hepatic ultrasound alterations were found in 56.5% and 48,9% of the overweight/obese and control group children, respectively. Presence of obesity was associated with high levels of triglycerides (OR = 4.6; P = 0.002). In the studied children, the risk of steatosis was related to a trend to a higher percentage of retinol inadequacy (OR = 2.8; p = 0.051); there was no association with thiobarbituric acid reactive substances, lipid profile, or insulin resistance. Conclusions: The high frequency of non-alcoholic fatty liver disease in both groups, evaluated by hepatic ultrasound, in low-socioeconomic level children, independent of nutritional condition and without significant association with insulin resistance, emphasizes that especially in developing countries, other risk factors such as micronutrient deficiencies (e.g. vitamin A) are involved.

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