Partial impairment of insulin receptor expression mimics fasting to prevent diet-induced fatty liver disease

In order to investigate the mechanism of the therapeutic effect of puerarin on non-alcoholic fatty liver disease, a non-alcoholic fatty disease male rat model was induced by a high fat diet, all rats were randomly divided into a blank group, model group, simavastatin group and puerarin group. After 4 weeks of drug treatment, the liver was slided to investigate pathological morphology. Elisa was used to measure the total cholesterol (TC), triglyeride (TG) in liver, and leptin content in serum. RT-PCR and Western blotting were employed to detect liver leptin mRNA receptor expression and P-JAK2, P-STAT3 expression levels in the liver respectively. The results showed that puerarin significantly decreased the TG, TC content in liver of the non-alcoholic fatty disease rats, ameliorated steatosis in liver, lowered liver inflammatory reaction, decreased leptin level in serum, and enhanced the expression of leptin receptor mRNA and P-JAK2/P-STAT3 level. All the results demonstrated that puerarin can exhibit therapeutic effect on non-alcoholic fatty liver disease by improving leptin signal transduction through JAK2/STAT3 pathways.

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Adiponectin Ligand and Receptor Expression in Omental Adipose Tissue of Morbidly Obese Patients with Non-Alcoholic Fatty Liver Disease (NAFLD)

The American Journal of Gastroenterology ◽

10.14309/00000434-201410002-00574 ◽

2014 ◽

Vol 109 ◽

pp. S168

Author(s):

Kameron Tavakolian ◽

James Estep ◽

Ancha Baranova ◽

Zachary Goodman ◽

Zobair Younossi

Keyword(s):

Adipose Tissue ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Receptor Expression ◽

Morbidly Obese ◽

Obese Patients ◽

Alcoholic Fatty Liver ◽

Omental Adipose Tissue ◽

Alcoholic Fatty Liver Disease

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INSULIN AND INSULIN RECEPTOR GENE POLYMORPHISMS AND SUSCEPTIBILITY TO NONALCOHOLIC FATTY LIVER DISEASE

Arquivos de Gastroenterologia ◽

10.1590/s0004-2803.202000000-39 ◽

2020 ◽

Vol 57 (2) ◽

pp. 203-208

Author(s):

Hossein NOBAKHT ◽

Touraj MAHMOUDI ◽

Mohammad SABZIKARIAN ◽

Seidamir Pasha TABAEIAN ◽

Gholamreza REZAMAND ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Liver Disease ◽

Fatty Liver ◽

Insulin Receptor ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Gene Polymorphisms ◽

Nonalcoholic Fatty Liver ◽

Glutamyl Transferase

ABSTRACT BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern defined by excessive hepatic fat content in the absence of excessive alcohol consumption. OBJECTIVE: Given the pivotal role of insulin resistance in NAFLD, we hypothesized that insulin (INS) and insulin receptor (INSR) gene polymorphisms may be associated with NAFLD risk. METHODS: A total of 312 subjects, including 153 cases with biopsy-proven NAFLD and 159 controls were enrolled in this case-control study. Four polymorphisms in INS (rs3842752, rs689) and INSR (rs1052371, rs1799817) genes were genotyped using PCR-RFLP method. RESULTS: The cases with NAFLD were older and had higher BMI, systolic blood pressure, diastolic blood pressure, as well as higher serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl transferase than the controls (P<0.001). The “TT” genotype of INSR rs1799817 compared with “CC” genotype occurred more frequently in the controls than the cases with NAFLD and the difference remained significant after adjustment for confounding factors (P=0.018; OR=0.10, 95%CI=0.02-0.76). However, no significant difference was found for INS rs3842752, INS rs689, and INSR rs1052371 gene polymorphisms between the cases with NAFLD and the controls either before or after adjustment for the confounders. CONCLUSION: These findings corroborate the hypothesis that genetic polymorphisms related to insulin resistance play a role in NAFLD susceptibility. Specifically, the INSR rs1799817 “TT” genotype had a protective effect for NAFLD. However, our results remain to be validated in other studies.

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GH-Dependent STAT5 Signaling Plays an Important Role in Hepatic Lipid Metabolism

Endocrinology ◽

10.1210/en.2010-0537 ◽

2011 ◽

Vol 152 (1) ◽

pp. 181-192 ◽

Cited By ~ 104

Author(s):

Johanna L. Barclay ◽

Caroline N. Nelson ◽

Mayumi Ishikawa ◽

Lauren A. Murray ◽

Linda M. Kerr ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Fatty Acid Synthase ◽

Dominant Negative ◽

Receptor Expression ◽

Gh Treatment ◽

Nonalcoholic Fatty Liver ◽

Mouse Hepatoma

Abstract GH deficiency is known to be clinically associated with a high incidence of nonalcoholic fatty liver disease, and this can be reversed by GH administration. Here we investigated the mechanistic basis for this phenomenon using engineered male mice lacking different signaling elements of the GH receptor, hepatic stat5a/b−/− mice and a mouse hepatoma line. We found deficient GH-dependent signal transducer and activator of transcription (STAT)-5 signaling correlates with steatosis, and through microarray analysis, quantitative PCR, and chromatin immunoprecipitation, identified putative targets of STAT5 signaling responsible for the steatosis seen on a normal diet. These targets were verified with liver-specific stat5a/b deletion in vivo, and in vitro we show that dominant-negative (DN) STAT5 increases lipid uptake in a mouse hepatoma line. Because loss of STAT5 signaling results in elevated STAT1 and STAT3 activity and intracellular lipid accumulation, we have used DN-STAT5a/b, DN-STAT1, constitutively active (CA)-STAT3, or addition of oleate/palmitate in the hepatoma line to assign which of these apply to individual targets in STAT5 signaling deficiency. These findings and published mouse models of steatosis enable us to propose elevated cd36, pparγ, and pgc1α/β expression as primary instigators of the steatosis along with elevated fatty acid synthase, lipoprotein lipase, and very low-density lipoprotein receptor expression. Decreased fgf21 and insig2 expression may also contribute. In conclusion, despite normal plasma free fatty acids and minimal obesity, absent GH activation leads to steatosis because activated STAT5 prevents hepatic steatosis. These results raise the possibility of low-dose GH treatment for nonalcoholic fatty liver disease.

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Association between insulin receptor gene exon 17 rs1799817 variant and risk of nonalcoholic fatty liver disease

Meta Gene ◽

10.1016/j.mgene.2016.10.012 ◽

2017 ◽

Vol 11 ◽

pp. 205-208

Author(s):

Touraj Mahmoudi ◽

Hossein Nobakht ◽

Reza Dabiri ◽

Iradj Maleki ◽

Pooneh Dehghan ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Insulin Receptor ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Receptor Gene ◽

Insulin Receptor Gene ◽

Nonalcoholic Fatty Liver ◽

Gene Exon

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Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease

Gut ◽

10.1136/gut.2009.190801 ◽

2010 ◽

Vol 59 (2) ◽

pp. 267-273 ◽

Cited By ~ 92

Author(s):

P Dongiovanni ◽

L Valenti ◽

R Rametta ◽

A K Daly ◽

V Nobili ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Insulin Receptor ◽

Liver Damage ◽

Fatty Liver Disease ◽

Insulin Signalling ◽

Receptor Activity ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Background/aimsThe aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, whose progression is associated with the severity of insulin resistance.Patients and methods702 patients with biopsy-proven NAFLD from Italy and the UK, and 310 healthy controls. The Lys121Gln ENPP1/PC-1 and the Gly972Arg IRS-1 polymorphisms were evaluated by restriction analysis. Fibrosis was evaluated according to Kleiner. Insulin signalling activity was evaluated by measuring phosphoAKT levels by western blotting in a subset of obese non-diabetic patients.ResultsThe ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidaemia and diabetes risk, respectively. The ENPP1 121Gln allele was significantly associated with increased prevalence of fibrosis stage >1 and >2, which was higher in subjects also positive for the 972Arg IRS-1 polymorphism. At multivariate analysis, the presence of the ENPP1 121Gln and IRS-1 972Arg polymorphisms was independently associated with fibrosis >1 (OR 1.55, 95% CI 1.24 to 1.97; and OR 1.57, 95% CI 1.12 to 2.23, respectively). Both polymorphisms were associated with a marked reduction of ∼70% of AKT activation status, reflecting insulin resistance and disease severity, in obese patients with NAFLD.ConclusionsThe ENPP1 121Gln and IRS-1 972Arg polymorphisms affecting insulin receptor activity predispose to liver damage and decrease hepatic insulin signalling in patients with NAFLD. Defective insulin signalling may play a causal role in the progression of liver damage in NAFLD.

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Effect of Seyoeum on Obesity, Insulin Resistance, and Nonalcoholic Fatty Liver Disease of High-Fat Diet-Fed C57BL/6 Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/4658543 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Hyun-Young Na ◽

Mi Hyeon Seol ◽

Mia Kim ◽

Byung-Cheol Lee

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Insulin Receptor ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Obese Mice ◽

High Fat ◽

Nonalcoholic Fatty Liver

Background. This study was performed to evaluate the effect of Seyoeum (SYE), a novel herbal meal replacement, on insulin resistance and nonalcoholic fatty liver disease (NAFLD) in obese mice fed with a high-fat diet (HFD).Methods. SYE contained six kinds of herbal powder such asCoix lacryma-jobi,Oryza sativa,Sesamum indicum,Glycine max,Liriope platyphylla,andDioscorea batatas. Male C57BL/6 mice were divided into four groups: normal chow (NC), HFD, SYE, and HFD plus SYE (HFD + SYE). The mice in groups other than NC were fed HFD for 9 weeks to induce obesity and then were fed each diet for 6 weeks. Clinical markers related to obesity, diabetes, and NAFLD were examined and gene expressions related to inflammation and insulin receptor were determined.Results. Compared with HFD group, body weight, serum glucose, serum insulin, HOMA-IR, total cholesterol, triglyceride, epididymal fat pad weight, liver weight, and inflammatory gene expression were significantly reduced in SYE group. Insulin receptor gene expression increased in SYE group.Conclusions. Based on these results, we conclude that SYE improved obesity and insulin resistance in high-fat fed obese mice. Our findings suggest that SYE could be a beneficial meal replacement through these antiobesity and anti-insulin resistance effects.

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