scholarly journals Downregulated microRNA-130b-5p prevents lipid accumulation and insulin resistance in a murine model of nonalcoholic fatty liver disease

2020 ◽  
Vol 319 (1) ◽  
pp. E34-E42
Author(s):  
Xiaonan Liu ◽  
Shuhong Chen ◽  
Lanju Zhang
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Model Assessment ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) amplifies the risk of various liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, and ultimately hepatocellular carcinoma. Accumulating evidence suggests the involvement of aberrant microRNAs (miRNAs or miRs) in the activation of cellular stress, inflammation, and fibrogenesis in hepatic cells at different stages of NAFLD and liver fibrosis. Here, we explored the potential role of miR-130b-5p in the pathogenesis of NAFLD, including lipid accumulation and insulin resistance, as well as the underlying mechanism. Initially, the expression of miR-130b-5p and insulin-like growth factor binding protein 2 (IGFBP2) was examined in the established high-fat diet-induced NAFLD mouse models. Then, the interaction between miR-130b-5p and IGFBP2 was validated using dual luciferase reporter assay. The effects of miR-130b-5p and IGFBP2 on lipid accumulation and insulin resistance, as well as the AKT pathway-related proteins, were evaluated using gain or loss-of-function approaches. miR-130b-5p was upregulated, and IGFBP2 was downregulated in liver tissues of NAFLD mice. miR-130b-5p targeted IGFBP2 and downregulated its expression. MiR-130b-5p inhibition or IGFBP2 overexpression reduced the expression of SREBP-1, LXRα, ChREBP, stearoyl CoA desaturase 1, acetyl CoA carboxylase 1, and fatty acid synthase, and levels of fasting blood glucose, fasting insulin, and homeostasis model assessment-insulin resistance, while increasing the ratio of p-AKT/AKT in NAFLD mice. Overall, downregulation of miR-130b-5p can prevent hepatic lipid accumulation and insulin resistance in NAFLD by activating IGFBP2-dependent AKT pathway, highlighting the potential use of anti-miR-130b-5p as therapeutic approaches for the prevention and treatment of NAFLD.

Nonalcoholic Fatty Liver Disease and Estimated Insulin Resistance in Obese Youth: A Mendelian Randomization Analysis

2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Anita Morandi ◽  
Anna Di Sessa ◽  
Chiara Zusi ◽  
Giuseppina Rosaria Umano ◽  
Dania El Mazloum ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Model Assessment ◽  
Causal Association ◽  
Nonalcoholic Fatty Liver

Abstract Context Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR) and predicts type 2 diabetes. Currently, it is uncertain whether NAFLD may directly cause IR or vice versa. Objective To test the hypothesis that NAFLD is causally related to IR. Design and Methods We performed a Mendelian randomization (MR) in 904 obese children/adolescents using an NAFLD-related genetic risk score (GRS) as an instrumental variable. We assessed NAFLD by ultrasonography and IR by homeostasis model assessment (HOMA-IR). We also interrogated the MAGIC Consortium dataset of 46 186 adults to assess the association between PNPLA3 rs738409 (ie, the most robust NAFLD-related polymorphism) and HOMA-IR, and we performed a 2-sample MR with 2 large datasets to test reverse causation (HOMA-IR increasing the risk of NAFLD). Results Nonalcoholic fatty liver disease prevalence increased by 20% for every increase in the GRS (β-coefficient = 0.20, P < 0.001), and NAFLD was associated with ln-HOMA-IR (β-coefficient = 0.28, P < 0.001). Thus, the expected increase in ln-HOMA-IR for every increase in the GRS (expected β-coefficient) was 0.056 (0.28*0.20) in the case of complete NAFLD-HOMA-IR causal association, and 0.042 in the case of 75% causality. In our cohort, the GRS did not predict ln-HOMA-IR (β-coefficient = 0.007, P = 0.75). In the MAGIC cohort, the PNPLA3 rs738409 did not associate with ln-HOMA-IR. The 2-sample MR failed to show a causal association between ln-HOMA-IR and NAFLD. Conclusions Our study shows that genetically-influenced NAFLD does not increase HOMA-IR, and genetically-influenced HOMA-IR does not increase the risk of NAFLD. Shared pathogenic pathways or NAFLD subtypes not “captured” by our MR design might underpin the association between NAFLD and HOMA-IR.

scholarly journals The Association between SOCS1−1656G>A Polymorphism, Insulin Resistance and Obesity in Nonalcoholic Fatty Liver Disease (NAFLD) Patients

2019 ◽  
Vol 8 (11) ◽  
pp. 1912 ◽  
Author(s):  
Agnieszka Kempinska-Podhorodecka ◽  
Ewa Wunsch ◽  
Piotr Milkiewicz ◽  
Ewa Stachowska ◽  
Malgorzata Milkiewicz
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Taqman Assay ◽  
Cytokine Signaling ◽  
Model Assessment ◽  
Nonalcoholic Fatty Liver ◽  
Risk Variants

Suppressor of cytokine signaling (SOCS) proteins prevent uncontrolled cytokine signaling and appear to play a role in the pathological processes behind obesity and insulin resistance. The polymorphism of the SOCS1 gene (rs243330, −1656G>A) is associated with obesity and glucose sensitivity. To estimate the effect of this SOCS1 gene polymorphism on nonalcoholic fatty liver disease (NAFLD) susceptibility, we performed a study on 138 patients with ultrasound-confirmed NAFLD and 1000 healthy blood donors. The relationship between the SOCS1−1656G>A polymorphism and serum biochemical parameters in NAFLD was additionally investigated. The SOCS1 variant was genotyped using a dedicated TaqMan assay. The frequency of rs243330 polymorphism did not differ between patients and controls. However, in a cohort of obese individuals (BMI ≥ 30 kg/m2) the occurrence of the G allele of the SOCS1−1656G>A polymorphism was strongly associated with NAFLD (odds ratio (OR) 1.6; 95% CI,1.1–2.5; p = 0.009), and carriers of the AA genotype have lower risk of developing NAFLD (OR 0.4; 95% CI, 0.2–0.7; p = 0.004). Overweight NAFLD patients who were carriers of GG genotypes had significantly lower levels of homeostasis model assessment of insulin resistance (HOMA-IR) values (p = 0.03 vs. AA), and the obese GG homozygotes had lower serum concertation of triglyceride (GG vs. AA; p = 0.02). Serum liver enzyme activities were not modified by the presence of SOCS1 risk variants. In conclusion, the observed phenotype of overweight NAFLD patients with non-elevated levels of TG and HOMA-IR, which is associated with genetic variants of SOCS1, provides a rationale for further research on the pathophysiology of fatty liver disease.

scholarly journals Nonalcoholic Fatty Liver Disease Relationship with Metabolic Syndrome in Class III Obesity Individuals

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
A. Cordeiro ◽  
S. E. Pereira ◽  
C. J. Saboya ◽  
A. Ramalho
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Blood Pressure Measurement ◽  
Model Assessment ◽  
Class Iii ◽  
Nonalcoholic Fatty Liver

Introduction. Obesity is represented mainly by abdominal obesity and insulin resistance (IR), both present in most individuals diagnosed with metabolic syndrome (MS). IR is the key risk factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD).Objective. To relate NAFLD to MS in class III obese individuals.Methodology. A descriptive cross-sectional study with class III obese individuals, aged ≥ 20–60 years. Blood pressure measurement, weight, height, body mass index (BMI), waist circumference (WC) and blood glucose, insulin, high-density lipoprotein cholesterol (HDL-c), and triglycerides data were obtained. HOMA-IR (homeostatic model assessment insulin resistance) calculation was carried out with a cutoff value of 2.71 for IR evaluation. The diagnosis of NAFLD was performed by liver biopsy and the diagnosis of MS was performed in accordance with the National Cholesterol Education Program/Adult Treatment Panel III (NCEPATP III).Results. Of the 50 individuals evaluated, 86% were women and BMI means were 45.4 ± 3.6 Kg/m2. The overall individuals had NAFLD, 70% steatosis, and 30% steatohepatitis. The diagnosis of MS occurred in 56% but showed no significant association with NAFLD (P=0.254). Triglycerides (178 ± 65.5 mg/dL) and insulin (28.2 ± 22.6 mcU/mL) mean values were significantly higher in steatohepatitis (P=0.002andP=0.042, resp.) compared to individuals with steatosis. IR was confirmed in 76% and showed a relationship with NAFLD severity.Conclusion. NAFLD was not related to MS; however, MS components, evaluated in isolation, as well as IR, were related to the presence and severity of NAFLD.

scholarly journals Insulin Resistance in Nonalcoholic Fatty Liver Disease: Experience from Bangladesh

2016 ◽  
Vol 4 (2) ◽  
pp. 86-91 ◽  
Author(s):  
Golam Azam ◽  
Shahinul Alam ◽  
SKM Nazmul Hasan ◽  
Sheikh Mohammad Noor E Alam ◽  
Jahangir Kabir ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Model Assessment ◽  
Nonalcoholic Fatty Liver ◽  
Homeostatic Model Assessment ◽  
Low Hdl ◽  
Study Population

Background: Insulin resistance (IR) has largely been hypothesized as central in multifactorial pathogenesis of nonalcoholic fatty liver disease (NAFLD). This study was aimed to explore the association of IR with NAFLD and nonalcoholic steatohepatitis (NASH).Methods: We enrolled 219 patients of NAFLD with sonographic evidence of fatty changes in liver excluding patients with alcohol intake and other causes of fatty change during June 2012 to July 2014.Liver biopsy was done for 110 patients with elevated ALT of >30 U/L for male and >18 U/L for female. We have measured IR by homeostatic model assessment of insulin resistance (HOMA-IR).Results: Age of the study population was 40.6 ± 10.0 years, male and female was 83 (37.9%) and 136 (62.1%), ALT was 42.0 (16-861) U/L, AST was 32 (16-608) U/L and GGT was 39 (10-243) U/L. According to Asian criteria 54 (25.9%) were non-obese, 139 (64.1%) had metabolic syndrome, 163 (74.8%) were hypertriglyceridemic, 200 (91.3%) had low HDL and 170 (77.4%) had high waist. Hypertensive and diabetic were 58 (26.7%) and 57 (26.1%) respectively. IR was 1.9±1.3 with the range of 0.4 to 9.3 and only 87 (39.7%) were above normal. Of the 110 biopsied, 65 (59.1%) had NASH. Normal and raised IR was associated with 32 (50.8%) and 33 (70.2%) NASH respectively (p < 0.05). Correlation between IR and steatosis, ballooning and fibrosis was not significant except lobular inflammation. IR was similar in NASH (2.2 ±1.6) and non NASH (1.9±1.6).Conclusion: Large proportion of NAFLD patients had normal IR. IR had inconsistent association with histological activity.Bangladesh Crit Care J September 2016; 4 (2): 86-91

scholarly journals Indole-3-Acetic Acid Alleviates Nonalcoholic Fatty Liver Disease in Mice via Attenuation of Hepatic Lipogenesis, and Oxidative and Inflammatory Stress

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2062 ◽  
Author(s):  
Yun Ji ◽  
Yuan Gao ◽  
Hong Chen ◽  
Yue Yin ◽  
Weizhen Zhang
Keyword(s):  
Insulin Resistance ◽  
Acetic Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Model Assessment ◽  
Nonalcoholic Fatty Liver ◽  
Inflammatory Stress ◽  
Indole 3 Acetic Acid

Recent evidences have linked indole-3-acetic acid (IAA), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However, data supporting IAA-mediated protection against nonalcoholic fatty liver disease (NAFLD) from an in vivo study is lacking. In this study, we assessed the role of IAA in attenuating high-fat diet (HFD)-induced NAFLD in male C57BL/6 mice. Administration of IAA (50 mg/kg body weight) by intraperitoneal injection was found to alleviate HFD-induced elevation in fasting blood glucose and homeostasis model assessment of insulin resistance (HOMA-IR) index as well as plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), and glutamic-pyruvic transaminase (GPT) activity. Histological examination further presented the protective effect of IAA on liver damage induced by HFD feeding. HFD-induced an increase in liver total triglycerides and cholesterol, together with the upregulation of genes related to lipogenesis including sterol regulatory element binding-protein 1 (Srebf1), steraroyl coenzyme decarboxylase 1 (Scd1), peroxisome proliferator-activated receptor gamma (PPARγ), acetyl-CoA carboxylase 1 (Acaca), and glycerol-3-phosphate acyltransferase, mitochondrial (Gpam), which were mitigated by IAA treatment. The results of reactive oxygen species (ROS) and malonaldehyde (MDA) level along with superoxide dismutase (SOD) activity and glutathione (GSH) content in liver tissue evidenced the protection of IAA against HFD-induced oxidative stress. Additionally, IAA attenuated the inflammatory response of liver in mice exposed to HFD as shown by the reduction in the F4/80-positive macrophage infiltration and the expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α). In conclusion, our findings uncover that IAA alleviates HFD-induced hepatotoxicity in mice, which proves to be associated with the amelioration in insulin resistance, lipid metabolism, and oxidative and inflammatory stress.

Combined treatments with metformin and phosphodiesterase inhibitors alleviate nonalcoholic fatty liver disease in high-fat diet fed rats: a comparative study

2020 ◽  
Vol 98 (8) ◽  
pp. 498-505
Author(s):  
Gehan H. Heeba ◽  
Reham M. El-Deen ◽  
Rania G. Abdel-latif ◽  
Mohamed M.A. Khalifa
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Phosphodiesterase Inhibitors ◽  
Model Assessment ◽  
High Fat ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is an excessive accumulation of fats in the liver resulting in hepatic inflammation and fibrous tissue formation along with insulin resistance. This study was designed to investigate the possible protective effects of metformin alone and in combination with different phosphodiesterase inhibitors (PDEIs). Rats were fed a high-fat diet (HFD) for 16 weeks to induce NAFLD. Starting from week 12, rats received metformin alone or in combination with pentoxifylline, cilostazol, or sildenafil. HFD administration resulted in hepatic steatosis and inflammation in rats. In addition, liver index, body composition index, activities of liver enzymes, and serum lipids deviated from normal. Further, significant elevations were recorded compared to control in terms of serum glucose, insulin, and HOMA-IR (homeostasis model assessment index for insulin resistance), oxidative stress parameters, hepatic TNF-α and NF-κB gene expression, and iNOS protein expression. Rats treated with metformin showed a significant improvement in the aforementioned parameters. However, the addition of pentoxifylline to metformin treatment synergized its action and produced a fortified effect against HFD-induced NAFLD better than other PDEIs. Data from this study indicated that combined treatment of metformin and pentoxifylline had the most remarkable ameliorated effects against HFD-induced NAFLD; further clinical investigations are needed to approve PDEIs for NAFLD treatment.

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