scholarly journals Young Adult LEW.1WR1 Rats, a Model of Liver FAT10 Overexpression, Develop Insulin Resistance and Fatty Liver With Age

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A514-A514
Author(s):  
Madushika M Wimalarathne ◽  
Luis D Mercado ◽  
Quiana C Wilkerson Vidal ◽  
James Wolfsberger ◽  
Victoria J McConnell ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Body Mass ◽  
Fat Mass ◽  
The Body ◽  
Liver Fat ◽  
Nonalcoholic Fatty Liver ◽  
Insulin Resistant ◽  
Human Lifespan ◽  
Insulin Tolerance

Abstract As human lifespan increases, comorbid conditions that impact quality of life have become a serious problem. FAT10 has been identified as a gene that when knocked out, improves age associated metabolic dysfunctions and increased longevity in mice (1). There is increased Fat10 expression in the liver in obesity (2,5). Providing evidence that fat10 expression may be important for triggering the transition to metabolic dysfunction in aging. Adult LEW.1WR1(1WR1) rats have increased body mass without excess abdominal fat mass compared to control rats (3). Yet, it was unclear where the excess mass was stored. We hypothesized that the 1WR1 rat would develop increased liver fat mass as a product of increased insulin resistance in response to increased liver fat10 expression over time. To test this hypothesis, we did insulin tolerance tests(7 weeks & 15 weeks), triglyceride assays, and histological analysis of the liver(23 weeks), in 1WR1 rats(n=7) and Wistar Furth (WF) rats(n=7) on control diets. We analyzed images using histological scoring for nonalcoholic fatty liver disease from the literature (4). We also assessed the slides for Mallory Denk bodies (MBs). The body mass of 1WR1 rats were increased compared to WF rat groups starting from the age of 7 weeks (391.4∓8.572g vs. 271.8∓11.62g; p <0.0006). 1WR1 rats became more insulin resistant with age, the 1WR1 rat group has increased AUC of 7 and 15 week Insulin Tolerance Tests (401.5∓23.54 vs. 245.3∓10.20 7w ITT1; p= 0.0728, 15w ITT2 328.2∓14.86 vs. 217.8∓9.; p <0.0003) compared to WF rats. 1WR1 rats have increased liver mass (11.85g∓0.7699g vs. 7.235g∓0.3864g; p=0.0006) liver triglyceride levels compared to WF rats (192.8∓21.8 mg/mL vs. 130.1∓13.075 mg/mL; p=0.0728). 1WR1 rats have increased steatosis scores(1.857∓0.2608 vs. 1.143∓0.1429;p= 0.0862) yet significantly reduced inflammatory foci level (2∓0.8165 vs. 3∓0;p= 0.007), most 1WR1 hepatocytes are enlarged (ballooned) and contained MBs compared to WF rats suggesting 1WR1 rats have already passed the early inflammation stage. Adult 1WR1 rats developed reduced insulin sensitivity and lipid accumulation in the liver. These data support our hypothesis that 1WR1 rats would develop increased liver fat and impaired insulin resistance in response to aging and show that this process may be inflammation driven. (1) Canaan et al.,PNAS. April 2014; 111 (14): 5313-5318.(2)Vidal et al., FASEB.2020, 34: 1-1,(3) Collins et al., J Endocr Soc. 2019;3(1),(4).Kleiner et al., Hepatology, 2005; 41 (6): 1313–1321,(5).Dali-Youcef et al., Hepatol Commun. 2019;3(9):1205-1220.

Abstract 05: Association of 25-Year Body Mass Index Trajectories Throughout Early Adulthood With Nonalcoholic Fatty Liver Disease in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Circulation ◽  
2017 ◽  
Vol 135 (suppl_1) ◽  
Author(s):  
Lisa B VanWagner ◽  
Sadiya Khan ◽  
Hongyan NIng ◽  
Juned Siddique ◽  
Cora E Lewis ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Body Mass ◽  
Fatty Liver Disease ◽  
Early Adulthood ◽  
Liver Fat ◽  
Nonalcoholic Fatty Liver ◽  
Bmi Trajectory

Background: Nonalcoholic Fatty Liver Disease (NAFLD) has increased in parallel with obesity, is a risk factor for cirrhosis and liver cancer, and has few effective treatments. Identifying modifiable risk factors for NAFLD development is essential to effectively design prevention programs. We tested whether trajectories of body mass index (BMI) change throughout early adulthood were associated with risk of prevalent NAFLD in midlife independent of current BMI. Methods: Participants from the CARDIA study, a prospective multicenter population-based biracial cohort of adults (baseline age 18-30 years), underwent BMI measurement at exam years 0, 2, 5, 7, 10, 15, 20, and 25. At Year 25 (Y25, 2010-2011), liver fat was assessed by computed tomography. NAFLD was identified after exclusion of other causes of liver fat (alcohol/hepatitis). Latent mixture modeling was used to identify 25-year trajectories in BMI percent (%) change relative to baseline BMI over time. Multivariable logistic regression models were used to assess associations between BMI trajectory group and prevalent NAFLD with adjustment for baseline or current Y25 BMI. Results: Among 4,423 participants, we identified 4 distinct trajectories of BMI %change: stable BMI (26.2% of the cohort, 25-year mean BMI Δ=0.7 kg/m 2 ), mild increase (46.0%, BMI Δ=5.2 kg/m 2 ), moderate increase (20.9%, BMI Δ=10.0 kg/m 2 ), and extreme increase (6.9%, BMI Δ=15.1 kg/m 2 ) (Figure). NAFLD prevalence at Y25 was higher with increasing BMI trajectory: 4.1%, 9.3%, 13.0%, and 17.6% (p-trend <0.0001). At baseline, 34.6% of participants had overweight or obesity. After adjustment for confounders, trajectories of greater BMI increase were associated with greater NAFLD prevalence independent of baseline or current Y25 BMI (Figure). Conclusion: Weight gain throughout adulthood is associated with greater prevalence of NAFLD in midlife independent of baseline or current BMI. These findings highlight weight maintenance throughout adulthood as a potential target for primary prevention of NAFLD.

scholarly journals Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Hannah E. Da Silva ◽  
Anastasia Teterina ◽  
Elena M. Comelli ◽  
Amel Taibi ◽  
Bianca M. Arendt ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Mass Index ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Body Mass ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver

scholarly journals Insulin Resistance, the Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease

2005 ◽  
Vol 90 (3) ◽  
pp. 1578-1582 ◽  
Author(s):  
F. Angelico ◽  
M. Del Ben ◽  
R. Conti ◽  
S. Francioso ◽  
K. Feole ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Oral Glucose ◽  
Nonalcoholic Fatty Liver ◽  
Insulin Resistant ◽  
The Metabolic Syndrome

Background/Aims: An association of nonalcoholic fatty liver disease with the insulin-resistant metabolic syndrome has been suggested. The aim of the study was to assess the association of fatty liver to different degrees of insulin resistance and secretion. Methods and Results: The study was performed in 308 alcohol- and virus-negative consecutive patients attending a metabolic clinic, who underwent a complete clinical and biochemical work-up including oral glucose tolerance test and routine liver ultrasonography. Steatosis was graded as absent/mild, moderate, and severe. In nondiabetic subjects, a progressive (P &lt; 0.05) increase in mean homeostasis model of insulin resistance was recorded from the group without steatosis to the groups with mild/moderate and severe steatosis. Severe steatosis was associated with the clustering of the five clinical and biochemical features proposed for the clinical diagnosis of the metabolic syndrome. Subjects with the metabolic syndrome with a more pronounced insulin resistance had a higher prevalence of severe steatosis (P &lt; 0.01) compared with those with homeostasis model of insulin resistance below the median. Conclusions: The findings stress the heterogeneous presentation of patients with the metabolic syndrome when the diagnosis is based on the broad Adult Treatment Panel III clinical criteria and demonstrate that those who are more insulin resistant have a higher prevalence of severe steatosis.

scholarly journals Hepatic Mitochondrial Remodeling is Mechanistically Linked to Insulin Resistance in Nonalcoholic Fatty Liver Disease

2020 ◽  
Author(s):  
Chris E. Shannon ◽  
Mukundan Ragavan ◽  
Juan Pablo Palavicini ◽  
Marcel Fourcaudot ◽  
Terry Bakewell ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Mitochondrial Function ◽  
Fatty Liver Disease ◽  
Tca Cycle ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver ◽  
Insulin Resistant ◽  
Mitochondrial Remodeling

ABSTRACTInsulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. We investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation in a rodent model of T2D / NAFLD. Livers from obese, insulin resistant mice displayed augmented mitochondrial content and increased TCA cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with pioglitazone mitigated pyruvate-driven TCA cycle activity and PDH activation via both covalent (PDK4 and PDP2) and allosteric (intracellular pyruvate availability) mechanisms. Interestingly, improvements in insulin sensitivity and mitochondrial function were entirely dissociated from changes in hepatic triglycerides, diacylglycerides or fatty acids. Instead, we show that the mitochondrial phospholipid cardiolipin undergoes pathological remodeling in livers from obese mice and that this is reversed by insulin sensitization. Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease.

scholarly journals The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease

Hepatology ◽  
2014 ◽  
Vol 61 (1) ◽  
pp. 153-160 ◽  
Author(s):  
Maryann Maximos ◽  
Fernando Bril ◽  
Paola Portillo Sanchez ◽  
Romina Lomonaco ◽  
Beverly Orsak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Liver Fat ◽  
Nonalcoholic Fatty Liver

scholarly journals Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine

2010 ◽  
Vol 299 (5) ◽  
pp. G1068-G1077 ◽  
Author(s):  
Elango Kathirvel ◽  
Kengathevy Morgan ◽  
Ganesh Nandgiri ◽  
Brian C. Sandoval ◽  
Marie A. Caudill ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Signaling Pathways ◽  
Hepg2 Cells ◽  
Fasting Glucose ◽  
Hepatic Insulin Resistance ◽  
Nonalcoholic Fatty Liver ◽  
Downstream Signaling ◽  
Insulin Resistant ◽  
Hepatic Fat

Nonalcoholic fatty liver (NAFL) is a common liver disease, associated with insulin resistance. Betaine has been tested as a treatment for NAFL in animal models and in small clinical trials, with mixed results. The present study aims to determine whether betaine treatment would prevent or treat NAFL in mice and to understand how betaine reverses hepatic insulin resistance. Male mice were fed a moderate high-fat diet (mHF) containing 20% of calories from fat for 7 (mHF) or 8 (mHF8) mo without betaine, with betaine (mHFB), or with betaine for the last 6 wk (mHF8B). Control mice were fed standard chow containing 9% of calories from fat for 7 mo (SF) or 8 mo (SF8). HepG2 cells were made insulin resistant and then studied with or without betaine. mHF mice had higher body weight, fasting glucose, insulin, and triglycerides and greater hepatic fat than SF mice. Betaine reduced fasting glucose, insulin, triglycerides, and hepatic fat. In the mHF8B group, betaine treatment significantly improved insulin resistance and hepatic steatosis. Hepatic betaine content significantly decreased in mHF and increased significantly in mHFB. Betaine treatment reversed the inhibition of hepatic insulin signaling in mHF and in insulin-resistant HepG2 cells, including normalization of insulin receptor substrate 1 (IRS1) phosphorylation and of downstream signaling pathways for gluconeogenesis and glycogen synthesis. Betaine treatment prevents and treats fatty liver in a moderate high-dietary-fat model of NAFL in mice. Betaine also reverses hepatic insulin resistance in part by increasing the activation of IRS1, with resultant improvement in downstream signaling pathways.

scholarly journals Elevated body mass index and fatty liver

2008 ◽  
Vol 136 (3-4) ◽  
pp. 122-125 ◽  
Author(s):  
Dragana Marovic
Keyword(s):  
Body Mass Index ◽  
Fatty Liver ◽  
Body Mass ◽  
Overweight And Obesity ◽  
The Body ◽  
Average Level ◽  
Nonalcoholic Fatty Liver ◽  
Elevated Body Mass Index ◽  
Significant Difference ◽  
The Difference

Introduction Obesity and overweight, expressed by elevated Body Mass Index (BMI), result from excessive consumption of fatty food and carbohydrates above the body needs. The fat from the blood, through free fatty acids, is taken directly into the liver. Objective The aim of this study was to examine correlation among the accepted ultrasonography findings of the fatty liver and the normal ultrasonography findings and the elevated average level of BMI and those with normal BMI in examinees in one investigation. All was done aimed at proving that the BMI is one of the direct factors of the increased occurence of fatty liver. METHOD The method of the investigation consisted of anthropometric measuring of height and weight on the basis of which there were established BMI values. Consequently, the examinees were divided in two groups: one with normal BMI (under 24.9 kg/m2) and the other with increased BMI (over 25 kg/m2). Fatty liver was diagnosed when the liver of the examinees was observed by ultrasonography. Thus there were given subgroups of the examinees, one with the findings of fatty liver and the second with a normal finding, without changes. After that, the obtained results were statistically analysed. Results It was found that the average level of BMI in the examinees was by two units higher in the subgroup with ultrasonography findings of fatty liver than the average value of BMI in the subgroup with the normal ultrasonography findings of the liver. The difference was tested by the Student's t-test and a significant difference was found. The difference in frequencies of the appearance of the finding of fatty liver in the subgroups was tested by ?2-test. A statistically significant difference was found in frequencies of the appearance of fatty liver in the subgroup with the increased value of BMI. Conclusion The increased BMI, which is represented by overweight and obesity, is one of the direct risk factors which cause fatty liver, checked by the US findings. Fatty liver can later progress to nonalcoholic fatty liver disease (NAFLD). .

scholarly journals Nonalcoholic Fatty Liver Disease in Nonobese Subjects of African Origin Has Atypical Metabolic Characteristics

2019 ◽  
Vol 3 (11) ◽  
pp. 2051-2063
Author(s):  
Debbie S Thompson ◽  
Ingrid A Tennant ◽  
Deanne P Soares ◽  
Clive Osmond ◽  
Chris D Byrne ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Liver Fat ◽  
Fasting Insulin ◽  
African Origin ◽  
Fetuin A ◽  
Nonalcoholic Fatty Liver

Abstract Background Nonobese nonalcoholic fatty liver disease is reported in several populations. However, because persons of African origin display unique fat accumulation, insulin resistance, and lipid profiles, we investigated fatty liver in nonobese persons of African origin. Method We recruited 78 urban Jamaican volunteers. CT was used to estimate liver and abdominal fat and dual-energy X-ray absorptiometry to measure body composition. Fasting blood was collected for lipids, alanine aminotransferase (ALT), adiponectin, and fetuin-A. Homeostatic model assessment of insulin resistance (HOMA-IR), whole-body insulin sensitivity index (WBISI), insulinogenic index (IGI), and oral disposition index (oDI) were calculated after a 75-g oral glucose tolerance test. Results Fifty-two percent of participants were male; mean (±SD) age was 28.5 ± 7.8 years, and body mass index was 22.4 ± 3.0 kg/m2. Mean liver attenuation (MLA) and liver/spleen (LS) ratio, both inversely correlated to liver fat, were 62.8 ± 4.3 HU and 1.2 ± 0.1, respectively; 3.8% of participants had liver fat >30% (LS ratio < 1). In age, sex, and BMI-adjusted correlations, MLA was negatively associated with weight (r = −0.30; P = 0.009) and height (r = −0.28; P = 0.017) and was associated with fasting glucose (r = 0.23; P = 0.05), fasting insulin (r = 0.42; P ≤ 0.001) and HOMA-IR (r = 0.35; P = 0.004). Serum lipids, ALT, adiponectin, fetuin-A, WBISI, IGI, and oDI were not associated with liver fat. Conclusions In nonobese Afro-Caribbean participants, greater liver fat was associated with weight and height and lower fasting insulin and hyperinsulinemia appears to be influential in the reduction of NAFLD. These findings may be influenced by ethnicity, body size, and method of estimating liver fat.

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