Insulin Resistance In Nonalcoholic Fatty Liver Disease Research Articles

Understanding Insulin Resistance in NAFLD: A Systematic Review and Meta-Analysis Focused on HOMA-IR in South Asians.

Non-alcoholic fatty liver disease (NAFLD), a metabolic condition, is becoming increasingly common in South Asia. While its clinical diagnosis primarily relies on sonography and altered hepatic biomarkers, the significance of non-hepatic indicators, such as Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), in relation to NAFLD requires further examination in the South Asian population due to ethnic differences in these markers. This study examined the relationship between insulin resistance, quantified using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and NAFLD, along with other non-hepatic biomarkers. A thorough literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the PubMed, Embase, and Google Scholar databases, yielding 287 articles. After applying the selection criteria and screening, 22 studies were selected for inclusion in the analysis. We extracted and meta-analyzed the data on HOMA-IR in patients with NAFLD, along with other relevant parameters. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of observational studies, whereas the RoB 2.0 tool was employed for randomized controlled trials (RCTs). The systematic review uncovered that individuals with NAFLD demonstrated statistically significant elevations in HOMA-IR levels, with a weighted mean difference (WMD) of 1.28 (95% confidence interval (CI): 1.00-1.58, I² = 98%, p < 0.0001) when compared to healthy subjects. Additionally, NAFLD patients showed markedly higher fasting blood glucose (FBG) levels, with a combined mean difference of 15.64 mg/dL (95% CI: 11.03-20.25, I² = 92%, p < 0.0001). The analysis also revealed increased triglyceride levels in NAFLD patients, with a pooled mean difference of 42.49 mg/dL (95% CI: 29.07-55.91, I² = 97%, p < 0.0001), and elevated C-reactive protein (CRP) levels, with a pooled mean difference of 2.17 mg/L (95% CI: 2.01-2.33, I² = 23%, p < 0.0001). Interestingly, subgroup analysis indicated that obese NAFLD patients exhibited significantly higher HOMA-IR levels than their non-obese counterparts, with a weighted mean difference of 5.85 (95% CI: 4.88-6.81, I² = 0%, p < 0.0001). Variations in study methodology, diagnostic techniques, and subject demographics were identified as sources of heterogeneity. The analysis found little evidence of publication bias, which lends credibility to the results. In South Asian populations, higher HOMA-IR, triglyceride-glucose (TyG) index, and CRP levels are associated with an increased risk of NAFLD. To improve the understanding and treatment of NAFLD in this specific demographic group, it is necessary to establish uniform diagnostic criteria and conduct additional studies, particularly RCTs.

Improving insulin resistance by sulforaphane via activating the Bacteroides and Lactobacillus SCFAs-GPR-GLP1 signal axis.

Background: Insulin resistance (IR) is closely associated with non-alcoholic fatty liver disease (NAFLD), and the gut microbiome contributes to the development of NAFLD. Sulforaphane (SFN) is a phytochemical in cruciferous vegetables that could improve lipid metabolism disorder. However, whether SFN can alleviate IR in NAFLD by regulating the intestinal flora remains unclear. Methods: SFN was administered to high fat diet (HFD)-fed Wistar rats for 10 weeks. Gut microbiota was analysed by 16S rRNA sequencing and the short chain fatty acids (SCFAs) by gas chromatography. The expression of tight junction protein and the numbers of Lactobacillus, Bacteroides and Bifidobacterium were determined by qPCR. The expression of G-protein-coupled receptor 41/43 (GPR41/43) was determined by western blot. A randomized controlled trial (RCT) was conducted in NAFLD patients with broccoli seed tablets (rich in SFN, 42 mg d-1) as intervention for 12 weeks. Thirty-six volunteers with abnormal glucose before the broccoli seed tablet treatment were selected in the intervention group to analyze their blood glucose, insulin, homeostasis model assessment-insulin resistance index (HOMA-IRI), homeostasis model assessment-insulin sensitivity index (HOMA-ISI) and glucagon-like peptide (GLP-1). Results: SFN reduced blood glucose and HOMA-IRI while increasing insulin sensitivity in HFD rats. SFN reduced glycogen synthase kinase 3 (GSK-3), phosphoenolpyruvate carboxykinase (PEPCK) activity, and phosphorylation of serine residues of IRS-2 induced by HFD. SFN reshaped the gut microbiota composition of HFD-induced rats and, especially, increased the content of Bacteroidaceae, Lactobacillaceae and Bifidobacteriaceae, which are related to the improvement from SFN of the blood glucose and HOMA-IRI. The increased numbers of Bacteroides and Lactobacillus were the targets of SFN to enhance the expression of tight junction proteins ZO-1 and occludin, thereby lowering lipopolysaccharide content to reduce inflammation, ultimately alleviating IR. Bacteroides and Lactobacillus produced SCFAs, which activated GPR41/43 to secrete GLP1. Moreover, it was also confirmed in RCT that SFN intervention increased the level of GLP1 in NAFLD patients, which was positively correlated with the reduction of blood glucose and HOMA-IR. Conclusions: SFN alleviated IR in NAFLD via the Bacteroides and Lactobacillus SCFAs-GPR41/43-GLP1 axis and protected the intestinal mucosal barrier to decrease inflammation.

Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease characterized by lipid accumulation and endoplasmic reticulum (ER) stress, while effective therapies targeting the specific characteristics of NAFLD are limited. Ufmylation is a newly found post-translational modification process that involves the attachment of the Ubiquitin-fold modifier 1 (UFM1) protein to its substrates via ufmylation modification system. Ufmylation regulates ER stress via modifying UFM1 binding protein 1 (UFBP1), suggesting a potential role for ufmylation in NAFLD pathogenesis. However, the precise role of ufmylation in NAFLD remains unclear. Herein, we aim to elucidate the impact of ufmylation on UFBP1 in NAFLD and explore the underlying mechanisms involved. We observed increased expression of UFM1-conjugated proteins and ufmylation modification system components in livers with steatosis derived from NAFLD patients and NAFLD models. Upregulation of ufmylation on hepatic proteins appeared to be an adaptive response to hepatic ER stress in NAFLD. In vitro, knocking down UFBP1 resulted in increased lipid accumulation and lipogenesis in hepatocytes treated with free fatty acids (FFA), which could be rescued by wild-type UFBP1 (WT UFBP1) but not by a mutant form of UFBP1 lacking the main ufmylation site lys267 (UFBP1 K267R). In vivo, ufmylation on UFBP1 ameliorated obesity, hepatic steatosis, hepatic lipogenesis, dyslipidemia, insulin resistance and liver damage in mice with NAFLD induced by a high fat diet (HFD). We also demonstrated that the downregulation of UFBP1 induced ER stress, whereas the reintroduction or overexpression of UFBP1 alleviated ER stress in a manner dependent on ufmylation in NAFLD. This mechanism could be responsible for the amelioration of aberrant hepatic lipogenesis and insulin resistance in NAFLD. Our data reveal a protective role of ufmylation on UFBP1 against NAFLD and offer a specific target for NAFLD treatment.

Huangqin decoction alleviates lipid metabolism disorders and insulin resistance in nonalcoholic fatty liver disease by triggering Sirt1/NF-κB pathway.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological entity characterized by intrahepatic ectopic steatosis. As a consequence of increased consumption of high-calorie diet and adoption of a sedentary lifestyle, the incidence of NAFLD has surpassed that of viral hepatitis, making it the most common cause of chronic liver disease globally. Huangqin decoction (HQD), a Chinese medicinal formulation that has been used clinically for thousands of years, has beneficial outcomes in patients with liver diseases, including NAFLD. However, the role and mechanism of action of HQD in lipid metabolism disorders and insulin resistance in NAFLD remain poorly understood. To evaluate the ameliorative effects of HQD in NAFLD, with a focus on lipid metabolism and insulin resistance, and to elucidate the underlying mechanism of action. High-fat diet-induced NAFLD rats and palmitic acid (PA)-stimulated HepG2 cells were used to investigate the effects of HQD and identify its potential mechanism of action. Phytochemicals in HQD were analyzed by high-performance liquid chromatography (HPLC) to identify the key components. Ten primary chemical components of HQD were identified by HPLC analysis. In vivo, HQD effectively prevented rats from gaining body and liver weight, improved the liver index, ameliorated hepatic histological aberrations, decreased transaminase and lipid profile disorders, and reduced the levels of pro-inflammatory factors and insulin resistance. In vitro studies revealed that HQD effectively alleviated PA-induced lipid accumulation, inflammation, and insulin resistance in HepG2 cells. In-depth investigation revealed that HQD triggers Sirt1/NF-κB pathway-modulated lipogenesis and inflammation, contributing to its beneficial actions, which was further corroborated by the addition of the Sirt1 antagonist EX-527 that compromised the favorable effects of HQD. In summary, our study confirmed that HQD mitigates lipid metabolism disorders and insulin resistance in NAFLD by triggering the Sirt1/NF-κB pathway.

Nonalcoholic fatty liver disease : Hepatic manifestations of metabolic syndrome

Nonalcoholic fatty liver disease (NAFLD) is nowadays the leading cause of chronic liver disease worldwide and shows astrong association with the metabolic syndrome. The NAFLD is asystemic disease associated with aplethora of extrahepatic manifestations and comorbidities, such as type2 diabetes, obesity and dyslipidemia. These extrahepatic disorders are related either to secondary effects of the associated obesity or to pathophysiological effects of insulin resistance in NAFLD. The three most common causes of the observed increased morbidity and mortality associated with NAFLD are cardiovascular diseases, liver diseases, such as cirrhosis, and cancer. In this overview, cardiovascular diseases, type2 diabetes mellitus and chronic kidney diseases in connection with NAFLD are discussed as examples, as well as tumor entities, in particular colon cancer, lung diseases (obstructive sleep apnea), endocrine diseases (hypothyroidism) and systemic phenomena associated with NAFLD (e.g. iron overload and thrombophilia). In addition to focusing on the pathogenesis of these extrahepatic manifestations, the clinical implications are highlighted. So far there are no drugs approved for the indication NAFLD in Germany. The new NAFLD S2kguidelines offer away out of the current "therapeutic nihilism". Diagnostic and therapeutic algorithms based on the metabolic comorbidities and the stage of fibrosis are designed with practical relevance and can be used in everyday medical practice. Therefore, clear basic measures and drug recommendations can be given for NAFLD depending on the comorbidities and stage of fibrosis.

Triglyceride and glucose index: a useful tool for non-alcoholic liver disease assessed by liver biopsy in patients with metabolic syndrome?

Introduction: Non-alcoholic fatty liver disease (NAFLD) is associated with metabolic impairments, being a component of metabolic syndrome. Considering the involvement of fat accumulation and insulin resistance in NAFLD, triglyceride and glucose (TyG) index was proposed as a marker of NAFLD progression. The “gold standard” for the evaluation of liver lesions characteristic for NAFLD remains the liver biopsy. The aim of this study was to establish the links between TyG index, assessing insulin resistance, and histopathological lesions of liver samples obtained by liver biopsy in patients with metabolic syndrome. Patients, Materials and Methods: We conducted a study over a period of three years, including 113 adult patients with metabolic syndrome in whom hepatic disorders were assessed by liver biopsy and insulin resistance was evaluated by TyG index. Results and Discussions: In our study, steatosis had a frequency of 92.03%, being identified 26 cases with mild steatosis, 48 with moderate steatosis and 31 with severe steatosis. Regarding non-alcoholic steatohepatitis (NASH), the frequency of this disorder in our study group was 29.2% in the subjects with liver steatosis, while liver fibrosis had a frequency of 53.09%. When we analyzed the relationships between TyG index and the presence of each type of lesion necessary for NASH diagnosis, we obtained statistically significant differences for the presence of hepatocyte ballooning (p=0.01) and a high statistically significance for the NAFLD activity score (NAS) (p<0.0001). Conclusions: TyG index is a facile tool that can be used to identify patients at risk for advanced NAFLD lesions evaluated by liver biopsy.

Effect of LncPVT1/miR-20a-5p on Lipid Metabolism and Insulin Resistance in NAFLD.

PurposeNonalcoholic fatty liver disease (NAFLD) is closely related to lipid metabolism and insulin resistance. The current research mainly attempted to verify the clinical value of LncRNA plasmacytoma variant translocation 1 (PVT1), and whether microRNA regulates lipid metabolism and insulin resistance to participate in NAFLD.Patients and Methods81 patients with NAFLD and 78 healthy individuals were enrolled in this study. In addition, C57BL/6 mice were fed a high-fat diet to establish NAFLD model in vivo. Serum PVT1 and miR-20a-5p expression in NAFLD patients and mice were assessed by RT-qPCR. ROC curves determine the diagnostic value of PVT1 and miR-20a-5p. NAFLD mice were subjected to IPGTT to detect changes in insulin sensitivity, and the common indicators of lipid metabolism and insulin resistance were also evaluated. Dual-luciferase reporter assay verified the regulation mechanism of PVT1 and miR-20a-5p.ResultsPVT1 was upregulated in NAFLD patients and mice, while miR-20a-5p was decreased. Their expression trends were similar in patients with HOMA-IR ≥2.5. What’s more, miR-20a-5p, FBG, ALT, and HOMA-IR were independently correlated with PVT1. And PVT1 and miR-20a-5p show high clinical diagnostic value. Bodyweight, insulin sensitivity, lipid metabolism inductors were increased in NAFLD mice, but these increases were attenuated by PVT1 elimination. Finally, miR-20a-5p might function as the possible miRNA target of PVT1 via the binding sites at 3ʹ-UTR and negatively regulated by it.ConclusionPVT1 and miR-20a-5p are potential clinical biomarkers of NAFLD, and PVT1 promotes the occurrence of NAFLD by regulating insulin sensitivity and lipid metabolism, which may be achieved by targeting miR-20a-5p.

Resveratrol Improves Liver Steatosis and Insulin Resistance in Non-alcoholic Fatty Liver Disease in Association With the Gut Microbiota.

Resveratrol (RSV) is a potential alternative therapy for non-alcoholic fatty liver disease (NAFLD) that has been evaluated in many clinical trials, but the mechanisms of RSV action have not been fully elucidated. Recent studies suggested that the gut microbiota is an important RSV target; therefore, we speculated that the gut microbiota might mediate the beneficial effects of RSV in NAFLD. To verify this hypothesis, we established a high-fat diet (HFD)-induced NAFLD mouse model, which was subjected to RSV gavage to evaluate the therapeutic effects. We observed that RSV reduced liver steatosis and insulin resistance in NAFLD. RSV significantly changed the diversity and composition of the gut microbiota according to 16S rRNA sequencing. Gut microbiota gene function prediction showed that the enrichment of pathways related to lipid and glucose metabolism decreased after RSV treatment. Furthermore, correlation analysis indicated that the improvements in NAFLD metabolic indicators were closely related to the altered gut microbiota. We further fermented RSV with the gut microbiota in vitro to verify that RSV directly affected the gut microbiota. Our data suggested that the gut microbiota might be an important target through which RSV exerts its anti-NAFLD effect.

Insulin resistance is positively associated with plasma cathepsin D activity in NAFLD patients.

Previous studies associated plasma cathepsin D (CTSD) activity with hepatic insulin resistance in overweight and obese humans. Insulin resistance is a major feature of non-alcoholic fatty liver disease (NAFLD) and is one of the multiple hits determining the progression towards non-alcoholic steatohepatitis (NASH). In line, we have previously demonstrated that plasma CTSD levels are increased in NASH patients. However, it is not known whether insulin resistance associates with plasma CTSD activity in NAFLD. To increase our understanding regarding the mechanisms by which insulin resistance mediates NAFLD, fifty-five liver biopsy or MRI-proven NAFLD patients (BMI>25kg/m2) were included to investigate the link between plasma CTSD activity to insulin resistance in NAFLD. We concluded that HOMA-IR and plasma insulin levels are independently associated with plasma CTSD activity in NAFLD patients (standardized coefficient β: 0.412, 95% Cl: 0.142~0.679, p=0.004 and standardized coefficient β: 0.495, 95% Cl: 0.236~0.758, p=0.000, respectively). Together with previous studies, these data suggest that insulin resistance may link to NAFLD via elevation of CTSD activity in plasma. As such, these data pave the way for testing CTSD inhibitors as a pharmacological treatment of NAFLD.

Combination of asprosin and adiponectin as a novel marker for diagnosing non-alcoholic fatty liver disease

Background and objectivePatients with non-alcoholic fatty liver disease (NAFLD) have insulin resistance and are at an increased risk of diabetes. Recent evidence suggests that asprosin–a novel hormone secreted by white adipose tissue–may play a role in the pathogenesis of insulin resistance. However, the role of asprosin in NAFLD remains unclear. This study aimed to determine whether serum asprosin level could be used as a biochemical marker for NAFLD diagnosis. MethodsForty-three untreated NAFLD patients and 50 sex- and age-matched healthy controls were included. Circulating serum asprosin and adiponectin (another adipokine) levels were detected by ELISA. Other metabolic parameters related to NAFLD were also determined. ResultsIncreased circulating serum asprosin and decreased serum adiponectin levels were found in NAFLD patients unlike in healthy controls. A positive correlation was observed between asprosin and platelet counts (PLT) (r = 0.3653, p = 0.015), fasting blood glucose (FBG) (r = 0.3592, p = 0.017), triglyceride (TG) levels (r = 0.3383, p = 0.025), serum albumin (ALB) levels (r = 0.3273, p = 0.030), and insulin resistance (HOMA-IR) (r = 0.4799, p = 0.001), whereas a negative correlation existed between adiponectin and TG levels in the NAFLD group. Multivariate linear regression showed that FBG and HOMA-IR were independently related to asprosin levels. Receiver operating characteristic (ROC) curves showed that asprosinAUC and adiponectinAUC were 0.735 (95%CI 0.633–0.836, P < 0.0001) and 0.702 (95%CI 0.597–0.807, p = 0.0007) respectively. Moreover, the combination of both biomarkers showed good sensitivity and specificity with AUC of 0.827, which was better than the single detection of asprosin or adiponectin. ConclusionHigh serum asprosin and low adiponectin level might be associated with the presence of insulin resistance in NAFLD, and the combination of asprosin and adiponectin could be a novel biomarker for diagnosing NAFLD. These data needed to be confirmed and extended in further large-population, well-designed clinical studies.

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

Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern defined by excessive hepatic fat content in the absence of excessive alcohol consumption. 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. 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. 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. 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.

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

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.

Association between diet quality indicators and nonalcoholic fatty liver disease: The FLiO study

AbstractIntroductionDietary components are contributing factors in the development of Nonalcoholic fatty liver disease (NAFLD). The glycaemic index (GI), glycaemic load (GL) and total antioxidant capacity (TAC) have been considered potential dietary tools influencing diet–disease relationships. The aim of this study was to evaluate associations of the dietary GI, GL, TAC and insulin resistance (IR) condition with hepatic fat in NAFLD adults.Material and methods: 112 overweight/obese adults with NAFLD (age: 50.8 ± 9 years old) were included in the trial. Dietary intake was assessed by a validated 137-item food frequency questionnaire (FFQ). Anthropometric, glycemic and lipid profiles, fatty liver quantification by magnetic resonance imaging (MRI) and IR measured by the Homeostatic Model Assessment of IR (HOMA-IR) were assessed at baseline. This study was registered as FLiO: Fatty Liver in Obesity study; NCT03183193.Results: The median of liver fat content by MRI was 6.4 (3.8–10.9) in the recruited population. Participants with higher liver fat content showed significantly increased values of glucose, insulin, HbA1c and HOMA-IR than those with lower liver fat content (p &lt; 0.05). Correlation analyses revealed relevant positive associations of hepatic fat with GI (r = 0.17; p = 0.077) and GL (r = 0.19; p = 0.047). Also, a negative association between liver fat content and TAC (r = -0.22; p = 0.023) was found. Linear regression analyses were used to examine the associations of hepatic fat and dietary quality indicators as well as IR adjusted for potential confounders (sex, age and physical activity). The final models showed that HOMA-IR, GI, GL and TAC were able to explain between 22.4 and 22.8 % (p &lt; 0.001) of the variability of liver fat content.DiscussionThe pathophysiology of NAFLD is thought to be associated with dietary determinants that contribute to metabolic dysregulation such as IR, ectopic liver fat deposition and hepatic damage. In accordance with other authors, we suggest that monitoring GI, GL and TAC may be useful approaches for the dietary treatment of NAFLD since they are related to hepatic fat. Additionally, it is important to highlight the essential role of IR in NAFLD as a key mediator in the development of NAFLD. Certainly, findings of the present study revealed a significant association of hepatic fat accumulation and IR.In summary, GI, GL and TAC are potential markers of diet quality, with an impact on susceptible population at hepatic risk.

PPARγ alleviated hepatocyte steatosis through reducing SOCS3 by inhibiting JAK2/STAT3 pathway

Peroxisome proliferator-activated receptor gamma (PPARγ) participates in the process of insulin resistance (IR), a crucial pathophysiology in non-alcoholic fatty liver disease (NAFLD). Meanwhile, suppressor of cytokine signaling3 (SOCS3) also regulates IR in NAFLD. Both PPARγ and SOCS3 play a role in NAFLD through regulating IR, while it is unclear whether these two proteins interact to regulate hepatic steatosis. PPARγ, SOCS3 and its associated JAK2/STAT3 pathway were analyzed using Kuppfer cells (KCs) treatment with LPS and BRL-3A cells treatment with palmitic acid, KC-conditioned medium (KCCM), PPARγ agonist rosiglitazone (ROZ) or JAK2 inhibitor AG490 to demonstrate the role of PPARγ and SOCS3 in hepatocytes steatosis. As LPS concentration increasing, phagocytosis activity of KCs decreased; but releasing of TNF-α and IL-6 increased. After treatment with KCCM, mRNA level of SOCS3, JAK2 and STAT3 as well as protein expression of SOCS3, p-JAK2 and p-STAT3 in steatosis BRL-3A cells increased significantly, which were inhibited by AG490 or ROZ treatment. Taken together, these results indicated that KCCM attributed to KCs dysfunction facilitated hepatocyte steatosis through promoting expressing SOCS3; but PPARγ agonist ROZ alleviated steatosis through reducing SOCS3 expression by inhibiting JAK2/STAT3 in hepatocytes.

Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease.

Insulin resistance is a key risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) and may lead to liver fibrosis. Natural killer (NK) cells are thought to exert an antifibrotic effect through their killing of activated hepatic stellate cells (HSCs). Here, we investigated how the interplay between NK cells and HSCs are modified by insulin resistance in NAFLD. Fresh peripheral blood NK cells (clusters of differentiation [CD]56dim, CD16+) were collected from 22 healthy adults and 72 patients with NAFLD not currently taking any medications and without signs of metabolic syndrome. NK cells were assessed for insulin receptor expressions and cytotoxic activity when cultured in medium with HSCs. Fibrosis severities in patients with NAFLD were correlated linearly with elevated serum proinflammatory cytokine expression and insulin resistance severity. At the same time, fibrosis severities inversely correlated with insulin receptor expressions on NK cells as well as with their cytotoxic activities determined by CD107a by flow cytometry. NK cells from donors exhibiting severe fibrosis and insulin resistance exhibited significant mammalian target of rapamycin and extracellular signal‐regulated kinase depletion (through NK cell western blot quantitation), increased apoptosis, and failure to attenuate HSC activation in vitro. While exposure to insulin stimulated the cytotoxic activity of healthy NK cells, rapamycin prevented this effect and reduced NK insulin receptor expressions. Conclusion: Elevated insulin levels in F1 and F2 fibrosis enhances NK cell cytotoxic activity toward HSCs and prevents fibrosis progression by insulin receptors and downstream mammalian target of rapamycin and extracellular signal‐regulated kinase pathways. At more advanced stages of insulin resistance (F3 and F4 fibrosis), impaired NK cell activity rooted in low insulin receptor expression and or low serum insulin levels could further deteriorate fibrosis and may likely lead to cirrhosis development. (Hepatology Communications 2018;2:285‐298)

Update on lipid species and paediatric nonalcoholic fatty liver disease.

To describe the recent advances in our understanding of fatty acids and lipids in paediatric nonalcoholic fatty liver disease (NAFLD) and their future implications. Data have been accumulated to suggest that ceramides are the main drivers of hepatic insulin resistance in NAFLD, and inhibition of ceramide synthesis improves histology in mice.Saturated fatty acids formed by de novo lipogenesis generate increased lipotoxicity compared with dietary-derived saturated fatty acids.Hepatic lipogenesis and associated insulin resistance have been found to be influenced by several novel proteins, including E2F1, cyclic AMP response element binding protein transcriptional coactivator 2, Raptor, and eukaryotic initiation factor 6. There are encouraging data from animal models that modulation of these could be therapeutic targets.Human and animal metabolomics and lipidomics data have been used to generate a lipid signature for NAFLD and nonalcoholic steatohepatitis. Serum lipidomics appears to correlate with hepatic lipidomics.Therapeutic trials of polyunsaturated fatty acids in children have had mixed results, with some reductions in noninvasive biomarkers. Multiple new pathways for drug targets have been identified, and use of lipidomics is likely to become a noninvasive method for assessing disease. However, much of the data for paediatric NAFLD are extrapolated from adult or animal studies.

Role of oxidative stress and insulin resistance in disease severity of non-alcoholic fatty liver disease.

Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to find the relation between oxidative stress parameters and histopathological findings in NAFLD patients with and without insulin resistance (IR). Thirty-two patients with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied (M/F: 17/15; mean age 46.5±11.4 years). Twenty-one NAFLD patients with IR were compared with 11 patients without IR. The fasting insulin level was measured, and the insulin resistance index was calculated using the homeostasis model assessment (HOMA) method. Malondialdehyde (MDA) and superoxide dismutase (SOD) activities were measured in tissue and serum specimens. Glutathione (GH) was measured in tissue homogenates. Nitric oxide (NO), vitamin E and C levels were measured in serum. Patients with IR had significantly higher tissue MDA levels (p=0.001) and significantly decreased tissue SOD and GH levels (p=0.001 and 0.002, respectively) than those without IR. The steatosis grade, necroinflammatory grade and stage were significantly higher in patients with IR (p=0.035, 0.003 and 0.001, respectively). HOMA IR significantly correlated with the necroinflammatory grade, stage, tissue MDA, SOD and GH (p=0.013, 0.001, 0.008, 0.001 and 0.001, respectively). Serum MDA (β=1.88, p=0.002), serum SOD (β=0.57, p=0.006), tissue MDA (β=0.22, p=0.006), tissue SOD (β=1.48, p=0.071) and stage (β=2.81, p=0.003) were independently associated with increased HOMA IR. Increased MDA [OR: 1.51; 95% CI: (1.03-2.22); p=0.034] was a risk factor for non-alcoholic steatohepatitis (NASH), and increased SOD activity had a preventive effect against NASH [OR: 0.008; 95% CI: (0.001-0.98); p=0.04]. This study shows that insulin resistance in NAFLD correlates with enhanced oxidative stress. Histopathological disease severity significantly correlated with oxidative stress parameters. These data show that NAFLD patients with IR may have increased risk for disease progression.

The risk of transient postprandial oxyhypoglycemia in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is frequently associated with insulin resistance (IR) and abnormalities in glucose metabolism. Prevalent postprandial hyperinsulinemia along with insulin resistance in NAFLD may lead to hypoglycemia. This study investigated the prevalence of postprandial oxyhypoglycemia in patients with NAFLD. The oral glucose tolerance test (OGTT) with 75g glucose was performed in 375 biopsy-proven NAFLD patients with prior unknown type 2 diabetes mellitus (DM). Serum glucose and insulin levels were measured for 3h after glucose loading and the clinical parameters were compared. Normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and DM were observed in 36, 36, and 28%, respectively. Hypoglycemia (≤70mg/dL) after 3h was observed in 14.4% of all patients. The rate of hypoglycemia was significantly higher in NGT (63% of NGT) than in IGT (30% of IGT) and DM (7% of DM) (P<0.05). In patients with hypoglycemia, the levels of insulin were significantly higher at 30 and 60min than those without hypoglycemia (P<0.05). By multivariate analysis, high-LDL cholesterolemia (P<0.05), low-HDL cholesterolemia (P<0.05), and fibrosis (P<0.05) were significant factors that contributed to hypoglycemia after 3h on 75g OGTT. A relatively higher proportion of NAFLD cases exhibited transient postprandial hypoglycemia after 3h on OGTT, especially in NAFLD patients with early-stage fibrosis. By performing 75g OGTT for 3h, hypoglycemia would be diagnosed earlier and the treatment intervention would decrease the progression of NAFLD and deterioration of glucose metabolism.

Effect of Alkaloids from Nelumbinis Plumula against Insulin Resistance of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice.

This study aimed to investigate the effects of total alkaloids from Nelumbinis Plumula (NPA) on insulin resistance (IR) of high-fat diet- (HFD-) induced nonalcoholic fatty liver disease (NAFLD). Rats were fed with HFD for 8 weeks to induce NAFLD. Then, the effect of NPA on ameliorating IR in HFD-induced NAFLD was evaluated. Fasting serum insulin was determined using an enzyme-linked immunosorbent assay (ELISA) kit for insulin following the manufacturer's protocol. Some inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were determined using ELISA kits to assess the inflammatory burden in rats. The results showed that HFD could induce a significant increase in blood glucose and IR in rats. However, rats treated with NPA (400 or 600 mg/kg) showed improved IR and reduction in serum inflammatory cytokines TNF-α and IL-6. Further investigation indicated that NPA could inhibit IR by restoring the insulin receptor substrate-1 (IRS-1) and suppressing the expression of c-Jun N-terminal kinase (JNK) phosphorylation. The present results supported the view that the pathogenesis of NAFLD was complex with inflammation, together with increasing serum glucose and IR. Also, JNK and IRS phosphorylation were suggested for their involvement in the modulating of IR during NAFLD progression. Therefore, NPA may serve as a potential natural remedy against IR in NAFLD.

Reduction of sitting time has a positive effect on the decrease of insulin resistance in patients with non-alcoholic fatty liver disease.

IntroductionNon-alcoholic fatty liver disease (NAFLD) affects a large part of the human population. One of the major environmental factors associated with the risk of NAFLD is the lack of physical activity.AimTo compare the level of physical activity and the insulin resistance in NAFLD patients.Material and methodsThirty patients with NAFLD underwent a six-month dietary intervention based on the principles of classical dietetics. Data about diet and physical activity was based on 72-hour nutrition diaries and International Physical Activity Questionnaire (IPAQ). Standard blood biochemical analyses were carried out before and after diet at the University Hospital Laboratory.ResultsThe study showed that total physical activity and physical activity in leisure time are negatively correlated with insulin resistance (HOMA-IR) (p < 0.05). Insulin (p < 0.05), body weight (p < 0.05), and waist-hip ratio (WHR) (p < 0.05) were also negatively correlated with physical activity in free time. In addition, we noticed a positive correlation between sitting time and the risk of insulin resistance, in the case of HOMA-IR and insulin concentration (p < 0.05).ConclusionsDietary intervention and a physical activity plan are important factors in the treatment of non-alcoholic fatty liver disease. Taking regular exercise increases insulin sensitivity and prevents further development of the disease. It seems that diet and physical activity are not the only one risk factors of NAFLD. Our study reveals that the reduction of sitting time has a positive effect on the level of insulin and it reduces insulin resistance in patients with NAFLD.