GADD34-deficient mice develop obesity, nonalcoholic fatty liver disease, hepatic carcinoma and insulin resistance.
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ABSTRACT:
SUBMITTER: Nishio N
PROVIDER: S-EPMC4551985 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high-HIS, mid-HIS, low-HIS), as assessed by the hyperinsulinemic-euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high-HIS group was identical to that of the non-NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low-HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high-HIS and low-HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis-aconitic acid, were significantly higher in the high-HIS group compared to the low-HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin-sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634-647).
| S-EPMC5721442 | biostudies-literature
Project description:BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.
| S-EPMC7269561 | biostudies-literature
Project description:Obese individuals are often at risk for nonalcoholic fatty liver disease (NAFLD), insulin resistance, type 2 diabetes (T2D), and cardiovascular diseases such as angina, thereby requiring combination therapies for their comorbidities. Ranolazine is a second-line antianginal agent that also improves glycemia, and our aim was to determine whether ranolazine modifies the progression of obesity-induced NAFLD. Twelve-week-old C57BL/6J male mice were fed a low-fat or high-fat diet for 10 weeks and then treated for 30 days with either vehicle control or ranolazine (50 mg/kg via daily s.c. injection). Glycemia was monitored via glucose/pyruvate/insulin tolerance testing, whereas in vivo metabolism was assessed via indirect calorimetry. Hepatic triacylglycerol content was quantified via the Bligh and Dyer method. Consistent with previous reports, ranolazine treatment reversed obesity-induced glucose intolerance, which was associated with reduced body weight and hepatic steatosis, as well as increased hepatic pyruvate dehydrogenase (PDH) activity. Ranolazine's actions on hepatic PDH activity may be directly mediated, as ranolazine treatment reduced PDH phosphorylation (indicative of increased PDH activity) in HepG2 cells. Therefore, in addition to mitigating angina, ranolazine also reverses NAFLD, which may contribute to its documented glucose-lowering actions, situating ranolazine as an ideal antianginal therapy for obese patients comorbid for NAFLD and T2D.
| S-EPMC6485361 | biostudies-literature
Project description:BACKGROUND AND AIMS:Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. METHODS:We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). RESULTS:Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. CONCLUSION:These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.
| S-EPMC5900872 | biostudies-other
Project description:BACKGROUND AND OBJECTIVES:Nonalcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic boys. Further, obesity and insulin resistance are major risk factors for NAFLD. No gene localization studies had been performed on children with biopsy-proven NAFLD. This study aims to identify genomic variants associated with increased adiposity and insulin resistance in a population of children with varying histologic severity of NAFLD. METHODS:We conducted a genome-wide association scan (GWAS) including 624,297 single-nucleotide polymorphisms (SNPs) distributed among all 22 autosomal chromosomes in 234 Hispanic boys (up to 18 years of age) who were consecutively recruited in a prospective cohort study in the Nonalcoholic Steatohepatitis Clinical Research Network Studies. Traits were examined quantitatively using linear regression. SNPs with P value <10 and a minor allele frequency >5% were considered potentially significant. RESULTS:Evaluated subjects had a median age of 12.0 years, body mass index (BMI) of 31.4, and hemoglobin A1C (Hgb A1C) of 5.3. The prevalence of NAFL, borderline NASH, and definite NASH were 23%, 53%, and 22%, respectively. The GWAS identified 10 SNPs that were associated with BMI z score, 6 within chromosome 2, and 1 within CAMK1D, which has a potential role in liver gluconeogenesis. In addition, the GWAS identified 9 novel variants associated with insulin resistance: HOMA-IR (6) and HbA1c (3). CONCLUSIONS:This study of Hispanic boys with biopsy-proven NAFLD with increased risk for the metabolic syndrome revealed novel genetic variants that are associated with obesity and insulin resistance.
| S-EPMC5916321 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common cause of chronic liver disease due to an increase in the prevalence of obesity. The development of NASH leads to an increase in morbidity and mortality. While the first line of treatment is lifestyle modifications, including dietary changes and increased physical activity, there are no approved pharmacological treatment agents for NAFLD and NASH currently. Due to its complex pathophysiology, different pathways are under investigation for drug development with the focus on metabolic pathways, inflammation, and slowing or reversing fibrosis. There are several agents advancing in clinical trials, and promising results have been seen with drugs that affect hepatic steatosis, inflammation, and fibrosis. This review will provide an overview on NAFLD and some of the mechanisms of disease that are being targeted with pharmacologic agents.
| S-EPMC6163009 | biostudies-other
Project description:The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. NAFLD management is mainly focused on weight loss, but the optimal characteristics of the diet demand further investigation. This study aims to evaluate the effects of two personalized energy-restricted diets on the liver status in overweight or obese subjects with NAFLD after a 6 months follow-up. Ninety-eight individuals from the Fatty Liver in Obesity (FLiO) study were randomized into two groups and followed different energy-restricted diets. Subjects were evaluated at baseline and after 6 months. Diet, anthropometry, body composition, and biochemical parameters were evaluated. Liver assessment included ultrasonography, Magnetic Resonance Imaging, elastography, and determination of transaminases. Both dietary groups significantly improved their metabolic and hepatic markers after the intervention, with no significant differences between them. Multivariate regression models evidenced a relationship between weight loss, adherence to the Mediterranean Diet (MedDiet), and a decrease in liver fat content, predicting up to 40.9% of its variability after 6 months. Moreover, the antioxidant capacity of the diet was inversely associated with liver fat content. Participants in the group with a higher adherence to the MedDiet showed a greater reduction in body weight, total fat mass, and hepatic fat. These results support the benefit of energy-restricted diets, high adherence to the MedDiet, and high antioxidant capacity of the diet for the management of NAFLD in individuals with overweight or obesity.
| S-EPMC6836315 | biostudies-literature
Project description:We comprehensively searched for the factors that may attribute to hepatic insulin sensitivity in the patients with NAFLD. Forty-three NAFLD patients were assessed for putative biomarkers in blood and urine, body composition, tissue lipid content, tissue insulin sensitivity by hyperinsulinemic-euglycemic clamp, hepatic histology and gene expressions using liver biopsies, and life styles. In results, the higher levels of plasma adiponectin, muscle insulin sensitivity, and adipose tissue insulin sensitivity positively, but the higher levels of HbA1c, ALT, and log converted high-sensitive CRP negatively correlated with hepatic insulin sensitivity. Interestingly, whole liver volume and hepatic lean volume corrected by body surface area (cm3/m2) showed significant negative correlation with hepatic insulin sensitivity, specifically in patients with T2DM.
2019-07-18 | GSE134438 | GEO
Project description:OBJECTIVE:Animal models and studies in adults have demonstrated that copper restriction increases severity of liver injury in nonalcoholic fatty liver disease (NAFLD). This has not been studied in children. We aimed to determine if lower tissue copper is associated with increased NAFLD severity in children. METHODS:This was a retrospective study of pediatric patients who had a liver biopsy including a hepatic copper quantitation. The primary outcome compared hepatic copper concentration in NAFLD versus non-NAFLD. Secondary outcomes compared hepatic copper levels against steatosis, fibrosis, lobular inflammation, balloon degeneration, and NAFLD activity score (NAS). RESULTS:The study analysis included 150 pediatric subjects (102 with NAFLD and 48 non-NAFLD). After adjusting for age, body mass index z score, gamma glutamyl transferase, alanine aminotransferase, and total bilirubin, NAFLD subjects had lower levels of hepatic copper than non-NAFLD (P?=?0.005). In addition, tissue copper concentration decreased as steatosis severity increased (P?<?0.001). Copper levels were not associated with degree of fibrosis, lobular inflammation, portal inflammation, or balloon degeneration. CONCLUSIONS:In this cohort of pediatric subjects with NAFLD, we observed decreased tissue copper levels in subjects with NAFLD when compared with non-NAFLD subjects. In addition, tissue copper levels were lower in subjects with nonalcoholic steatohepatitis, a more severe form of the disease, when compared with steatosis alone. Further studies are needed to explore the relationship between copper levels and NAFLD progression.
| S-EPMC5492896 | biostudies-literature
Project description:Emerging data highlight the critical role for the innate immune system in the progression of nonalcoholic fatty liver disease (NAFLD). Connexin 32 (Cx32), the primary liver gap junction protein, is capable of modulating hepatic innate immune responses and has been studied in dietary animal models of steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human NAFLD in a histologically characterized cohort of 362 patients with NAFLD. We also studied the hepatic expression of the genes and proteins known to interact with Cx32 (known as the connexome) in patients with NAFLD. Last, we used three independent dietary mouse models of nonalcoholic steatohepatitis to investigate the role of Cx32 in the development of steatohepatitis and fibrosis. In a univariate analysis, we found that Cx32 hepatic expression associates with each component of the NAFLD activity score and fibrosis severity. Multivariate analysis revealed that Cx32 expression most closely associated with the NAFLD activity score and fibrosis compared to known risk factors for the disease. Furthermore, by analyzing the connexome, we identified novel genes related to Cx32 that associate with NAFLD progression. Finally, we demonstrated that Cx32 deficiency protects against liver injury, inflammation, and fibrosis in three murine models of nonalcoholic steatohepatitis by limiting initial diet-induced hepatoxicity and subsequent increases in intestinal permeability. Conclusion: Hepatic expression of Cx32 strongly associates with steatohepatitis and fibrosis in patients with NAFLD. We also identify novel genes associated with NAFLD and suggest that Cx32 plays a role in promoting NAFLD development. (Hepatology Communications 2018;2:786-797).
| S-EPMC6123534 | biostudies-literature