scholarly journals WW domain-binding protein 2 overexpression prevents diet-induced liver steatosis and insulin resistance through AMPKβ1

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Zhe Zheng ◽  
Yue Li ◽  
Siyuan Fan ◽  
Jie An ◽  
Xi Luo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Binding Protein ◽  
Liver Steatosis ◽  
Fat Deposition ◽  
Liver Fat ◽  
Future Research ◽  
Ww Domain ◽  
Important Relationship

AbstractNonalcoholic fatty liver disease (NAFLD) is prevalent clinically and can lead to more serious chronic liver disease. However, the pathological mechanism is still unclear, and thus, there are no approved drugs on the market. Transcriptional coactivator WW domain-binding protein 2 (WBP2) is a newly discovered oncogene that has an important relationship with the occurrence and development of breast cancer and mediates the interaction between Wnt and various other signaling pathways. The expression level of WBP2 was decreased in NAFLD. Overexpression of WBP2 with AAV in vivo alleviated liver fat deposition and insulin resistance induced by a high-fat diet (HFD). Knockdown of WBP2 with AAV aggravated HFD-induced fatty liver and insulin resistance. In vitro experiments showed that in the human normal hepatocyte cell line LO2 and primary hepatocytes isolated from mice, overexpression of WBP2 reduced fat deposition, and knocking out or knocking down WBP2 aggravated PA-induced fat deposition. Through mass spectrometry, we found that WBP2 can bind to AMPKβ1, and by mutating AMPKβ1, we found that WBP2 can induce phosphorylation of AMPKβ1 at S108 and then activate the AMPK pathway to affect lipid metabolism. The effect of WBP2 on NAFLD provides a possible new direction for future research on NAFLD.

scholarly journals Retinol binding protein-4 as a serum biomarker of intrahepatic lipid content in obese children--preliminary report.

2011 ◽  
Vol 58 (1) ◽  
Author(s):  
Anna Romanowska ◽  
Dariusz M Lebensztejn ◽  
Elżbieta Skiba ◽  
Eugeniusz Tarasów ◽  
Maciej Kaczmarski
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Serum Level ◽  
Fatty Liver ◽  
Lipid Content ◽  
Binding Protein ◽  
Liver Steatosis ◽  
Retinol Binding Protein ◽  
Obese Children ◽  
Intrahepatic Lipid

Obesity, insulin resistance and dyslipidemia are the most significant risk factors of non-alcoholic fatty liver disease (NAFLD) but the role of adipokines in the pathogenesis of this disease is not clear. Assessment of retinol binding protein (RBP-4) seems to be promising because data from animal and human studies suggest its role in the pathomechanism of insulin resistance. Therefore, the aim of the study was to evaluate the serum levels of RBP-4 in children with NAFLD. Fasting serum level of RBP-4 was determined in 42 obese children with suspected liver disease and 20 lean controls. The degree of liver steatosis was graded in ultrasound according to Saverymuttu. The intrahepatic lipid content was assessed noninvasively in a semiquantitative fashion using ¹HMR spectroscopy (1.5-T scanner with PRESS sequence). Fatty liver was confirmed in 30 children by ultrasonography (16 of them had also increased alanine transaminase (ALT) activity). Serum concentrations of RBP-4 were significantly higher in obese children with NAFLD compared to controls. Significant correlations were found between RBP-4 level and ultrasonographic grade of liver steatosis, intrahepatic lipid content (¹HMRS) and triglycerides level, while the serum level of RBP-4 was not significantly higher in children with advanced liver steatosis (grade 2-3, n = 11) compared to patients with mild steatosis (grade 1, n = 19). The ability of RBP-4 to differentiate children with advanced liver steatosis from those with mild steatosis was not significant. RBP-4 can be considered as a convenient serum marker of intrahepatic lipid content in obese children.

scholarly journals Response of Inflammatory Biomarkers to 10 Weeks of Aerobic Resistance Training in Inactive Postmenopausal Women with Non-alcoholic Fatty Liver

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Masumeh Norouzpour ◽  
Sayed Mohammad Marandi ◽  
Mohsen Ghanbarzadeh ◽  
Abbasali Zare Maivan
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Resistance Training ◽  
Fatty Liver ◽  
Postmenopausal Women ◽  
Fatty Liver Disease ◽  
Negative Relationship ◽  
Inflammatory Biomarkers ◽  
Liver Fat ◽  
Alcoholic Fatty Liver

Background: Research evidence shows that non-alcoholic fatty liver disease (NAFLD) is closely related to inflammation. Objectives: This study aimed to evaluate the response of inflammatory biomarkers to 10 weeks of aerobic resistance exercise in inactive postmenopausal women with NAFLD. Methods: In this purposeful quasi-experimental study, conducted in Mahshahr, Iran, in 2019, 24 inactive women aged 50 - 68 years who were diagnosed with fatty liver disease by ultrasound were randomly divided into training or control groups. The training group performed aerobic resistance training for 10 weeks using treadmills and bodybuilding machines. At the beginning and end of the study, serum interleukin 18 (IL18), interleukin 10 (IL10), and other blood parameters were measured, and the subjects underwent liver ultrasound and anthropometric evaluations. Results: The results of intergroup ANCOVA, intragroup paired t-test, and Wilcoxon showed that in response to 10 weeks of training, IL18 levels, anthropometric parameters, insulin resistance (HOMA-IR), liver enzymes, fasting glucose, triglyceride (TG), and liver fat were significantly decreased and plasma IL10 was significantly increased when compared to baseline results (P < 0.05). Also, the results of the Spearman correlation test showed a significant positive relationship between IL18 and waist circumference (WC), alanine aminotransferase (ALT), and HOMA-IR and a significant negative relationship between IL10 and weight, WC, TG, HOMA-IR, and liver fat (P < 0.05). Conclusions: Ten weeks of aerobic resistance training has a significant effect on reducing serum IL18 and increasing IL10 levels in postmenopausal women with fatty liver and can be effective in improving NAFLD by losing weight, improving body composition, and reducing insulin resistance.

scholarly journals Metabolic Syndrome (MetS) as a Predictor of Fatty Liver in HIV Infected Adults from the Miami Adult Studies on HIV (MASH) Cohort (FS12-06-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Colby Teeman ◽  
Yongjun Huang ◽  
Qingyun Liu ◽  
Jacqueline Hernandez ◽  
Javier Tamargo ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Liver Disease ◽  
Fatty Liver ◽  
Liver Steatosis ◽  
Liver Fat ◽  
Proton Density ◽  
People Living With Hiv ◽  
Serum Triglycerides ◽  
Significant Difference ◽  
Stage 1

Abstract Objectives One of the major comorbidities among people living with HIV (PLWH) is liver disease. MetS is common in this population and may also play a role in the development of liver disease. In order to better understand the mechanisms of liver disease in PLWH, it is important to investigate the relationship between components of MetS and the risk of fatty liver, an early precursor to liver disease. The objective of this study was to determine if the 5 criteria used to diagnose MetS contribute to liver steatosis. Methods Crossectional analyses of data from the MASH cohort were analyzed. Waist circumference (WC) and blood pressure (BP) were measured by a research nurse. Serum triglycerides (TRG), glucose (GLU), and HDL were determined in fasting by LabCorp. Liver fat % was estimated with proton density fat fraction using Magnetic Resonance Elastography conducted on a 3T Siemens MAGNETOM Prisma MRI. Liver fat >5% was defined as stage 1 steatosis. Components of MetS were taken from the NCEP ATP III definition of MetS. Spearman correlations and logistic regression were used for analyses. Results A total of 324 PLWH aged 53.5 ± 7.5 years were included. Liver fat% was correlated with WC (r = 0.394, P < 0.001), TRG (r = 0.332, P < 0.001), GLU (r = 0.358, P < 0.001), and systolic BP (r = 0.183, P = 0.011), inversely correlated with HDL (r = −0.236, P = 0.001), and trended toward significance with diastolic BP (r = 0.133, P = 0.065). Participants with stage 1 steatosis had a larger WC (41.02in ± 5.3 vs 36.95 ± 5.5, P = 0.001), higher TRG (210.3 mg/dL ± 173.9 vs 121.3 ± 67.9, P = 0.002), and higher GLU (126.1 mg/dL ± 77.7 vs 93.92 ± 50.8, P = 0.001) than those without steatosis. No significant difference was found for HDL cholesterol, SBP, or DBP. A logistic regression model that included all 5 MetS criteria and was controlled for age, gender, and alcohol AUDIT score >8 found that WC (OR 1.11, 95% CI 1.01–1.23, P = 0.030), TRG (OR 1.01, 95% CI 1.00–1.01, P = 0.040), and GLU (OR 1.01, 95% CI 1.00–1.03, P = 0.033) are significant predictors of stage 1 steatosis. Conclusions WC, TRG, and GLU, three of the 5 criteria for diagnosing MetS were significant predictors of stage 1 steatosis in PLWH. Future studies investigating the risk of liver disease progression in PLWH need to account for these confounding factors as they explore HIV specific mechanisms for liver disease. Funding Sources National Institutes on Drug Abuse #5UO1DA040381.

scholarly journals Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Paola Dongiovanni ◽  
Stefano Romeo ◽  
Luca Valenti
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Association Studies ◽  
Liver Steatosis ◽  
Liver Fat ◽  
Genome Wide Association Studies ◽  
Very Low Density Lipoproteins ◽  
Fat Accumulation ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Fat

Liver fat accumulation generally related to systemic insulin resistance characterizes nonalcoholic fatty liver disease (NAFLD), which in the presence of nonalcoholic steatohepatitis (NASH) can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease in Western countries. Epidemiological, familial, and twin studies provide evidence for a strong genetic component of NAFLD susceptibility. Recently, genome-wide association studies led to the identification of the major inherited determinants of hepatic fat accumulation:patatin-like phospholipase domain-containing 3 (PNPLA3)I148M gene andtransmembrane 6 superfamily member 2 (TM6SF2)E167K gene variants, involved in lipid droplets remodelling and very low-density lipoproteins secretion, are the major determinants of interindividual differences in liver steatosis, and susceptibility to progressive NASH. In this review, we aimed to provide an overview of recent insights into the genetics of hepatic fat accumulation and steatohepatitis.

scholarly journals The value of the triglyceride-glucose index in the diagnosis of insulin resistance in early forms of non-alcoholic fatty liver disease

2021 ◽  
pp. 43-48
Author(s):  
A. A. Shipovskaya ◽  
N. A. Larina ◽  
I. V. Kurbatova ◽  
O. P. Dudanova
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Liver Steatosis ◽  
Cytokeratin 18 ◽  
Alcoholic Fatty Liver ◽  
Triglyceride Glucose Index ◽  
Tnf Α ◽  
Alcoholic Fatty Liver Disease

The goal. To determine the value of the triglyceride glucose index (TGI) for the diagnosis of insulin resistance (IR) in early forms of non-alcoholic fatty liver disease (NAFLD).Materials and methods. 99 patients with NAFLD were examined: 38 (38.4%) with liver steatosis (LS) and 61 (61.6%) with steatohepatitis (SH). TGI was determined by the formula — In [fasting TG (mg / dl) × fasting glucose (mg / dl) / 2], patients with LS and SH were divided into quartiles (Q1-Q4) by increasing TGI levels with an assessment of liver tests, insulin levels (“Insulin TEST System”, Monobind Inc., USA), HOMA-IR, fragments of cytokeratin-18 (FCK-18) ("TPS ELISA, Biotech”, Sweden) and TNF-α (“Human TNFα Platinum” ELISA, eBioscience, Austria).Results. In patients with LS with a TGI increase from Q1 to Q4, HOMA-IR increased from 1.12 ± 0.48 to 6.02 ± 3.15 (p <0.05), a direct relationship was found between these indicators — r = 0.52 (p = 0.03). TGI also correlated with waist circumference — r = 0.81 (p = 0.01), cholesterol — r = 0.51 (p = 0.002), alkaline phosphatase — r = 0.41 (p = 0.02). In patients with SH, from Q1 to Q4, HOMA-IR increased from 3.15 ± 1.8 to 6.2 ± 3.04 (p <0.05), but there was no significant correlation between HOMA-IR and TGI. The levels of FCK-18 increased from Q1 to Q4-139.82 ± 72.45 to 359.75 ± 189.03 U / L (p <0.05) and TNF-α — from 6.38 ± 1.25 pg / ml up to 7.75 ± 1.09 pg / ml (p <0.05). There was a connection between TGI and the level of a marker of hepatocyte apoptosis — FCK-18 — r = 0.43 (p = 0.004).Conclusion. In liver steatosis, TGI has demonstrated its diagnostic role as a surrogate marker of insulin resistance, correlating with HOMA-IR. In steatohepatitis, TGI reflected the degree of hepatocytic apoptosis, correlating with fragments of cytokeratin-18.

scholarly journals Hepatic p38 activation modulates systemic metabolism through FGF21-mediated interorgan communication

2021 ◽  
Author(s):  
Wei Liu ◽  
Chao Sun ◽  
Ying Yan ◽  
Hongchao Cao ◽  
Zhoumin Niu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Liver Steatosis ◽  
Dependent Manner ◽  
Peripheral Tissues ◽  
Nonalcoholic Fatty Liver ◽  
Protein Levels

The mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38a- and FGF21-dependent manner. Mechanistically, through increasing the FGF21 production from liver, hepatic p38 activation increases the influx of fatty acids from adipose tissue to liver, leading to hepatic ectopic lipid accumulation and insulin resistance. Although hepatic p38 activation exhibits favorable effects in peripheral tissues, it impairs the hepatic FGF21 action by facilitating the ubiquitination and degradation of FGF21 receptor cofactor b-Klotho. Consistently, we show that p38 phosphorylation and FGF21 expression are increased, b-Klotho protein levels are decreased in the fatty liver of either mice or patients. In conclusion, our study reveals previously undescribed effects of hepatic p38 activation on systemic metabolism and provides new insights into the roles of hepatic p38a, FGF21, and b-Klotho in the pathogenesis of nonalcoholic fatty liver disease.

scholarly journals Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease and, Hepatic Fibrosis, and Insulin Resistance in Mice

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3532
Author(s):  
Sergio Quesada-Vázquez ◽  
Marina Colom-Pellicer ◽  
Èlia Navarro-Masip ◽  
Gerard Aragonès ◽  
Josep M. Del Bas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Fibrosis ◽  
Fatty Liver Disease ◽  
Liver Steatosis ◽  
Alcoholic Fatty Liver ◽  
Specific Combination ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.

scholarly journals Liver steatosis, but not fibrosis, is associated with insulin resistance in nonalcoholic fatty liver disease

2007 ◽  
Vol 42 (4) ◽  
pp. 312-317 ◽  
Author(s):  
Masaru Sakurai ◽  
Toshinari Takamura ◽  
Tsuguhito Ota ◽  
Hitoshi Ando ◽  
Hiroshi Akahori ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Liver Steatosis ◽  
Nonalcoholic Fatty Liver

Rhein ameliorates fatty liver disease through negative energy balance, hepatic lipogenic regulation, and immunomodulation in diet-induced obese mice

2011 ◽  
Vol 300 (5) ◽  
pp. E886-E893 ◽  
Author(s):  
Xiaoyan Sheng ◽  
Min Wang ◽  
Meng Lu ◽  
Beili Xi ◽  
Hongguang Sheng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Liver Disease ◽  
Energy Balance ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Binding Protein ◽  
Negative Energy ◽  
Negative Energy Balance

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and inflammatory disorders. In this study, we tested the effect of rhein, a lipophilic anthraquinone derived from a traditional Chinese herbal medicine Rheum palmatum L., on NAFLD-associated hepatic steatosis, insulin resistance, and the T helper (Th)1/Th2 cytokine imbalance in high-fat diet-induced obese (DIO) mice. We found that oral administration of rhein for 40 days significantly increased energy expenditure, reduced body weight, particularly body fat content, improved insulin resistance, and lowered circulating cholesterol levels in DIO mice without affecting food intake. Rhein treatment also reduced liver triglyceride levels, reversed hepatic steatosis, and normalized alanine aminotransferase (ALT) levels in these mice. Gene analysis and Western blot showed that rhein markedly suppressed the expression of the lipogenic enzyme sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes in the liver. Luciferase reporter assay revealed that rhein suppressed the transcriptional activity of SREBP-1c through its upstream regulator, liver X receptor (LXR). This suggests that rhein exerts its effects by targeting LXR, which is also supported by its inability to reduce body weight in LXR knockout mice. Moreover, multiplex ELISA displayed a downregulated Th1 response after rhein treatment. Rhein shifted the Th1/Th2 responses by inhibiting T-box expressed in T-cells (T-bet) expression and enhancing GATA-binding protein-3 (GATA-3) expression through increased signal transducer and activator of transcription 6 (STAT6) phosphorylation. These data indicate that rhein ameliorated NAFLD and associated disorders through LXR-mediated negative energy balance, metabolic regulatory pathways, and immunomodulatory activities involved in hepatic steatosis. The combined effects of rhein to target hepatic metabolic and immune pathways may be beneficial for complex metabolic diseases such as NAFLD.

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