Nitrate containing vegetables and dietary nitrate and nonalcoholic fatty liver disease: a case control study.

BACKGROUND: Vegetables is the main sources of dietary nitrate. Studies suggested the potential link between nitrate content of vegetables and reduce the risk of chronic diseases. We aimed to assess the association between nitrate-containing vegetables (NCVs) with odds of nonalcoholic fatty liver diseases (NAFLD) in Iranian adults. METHOD: This case-control study was performed on a total of 225 newly diagnosed NAFLD cases and 450 controls aged 20-60 years. Individuals' dietary intakes were determined using a valid and reliable food frequency questionnaire. RESULTS: The mean ± SD age and BMI of participants were 38.1 ± 8.8 years and 26.8 ± 4.3 kg/m2, respectively. In the fully adjusted model, the odds of NAFLD were decreased across tertiles of total NCVs [(adjusted OR: 0.20, 95%CI: 0.10-0.40), (Ptrend <  0.001)] and low-nitrate vegetables [(adjusted OR: 0.22, 95%CI: 0.11-0.48), (Ptrend <  0.001)]. Our results showed that each one SD increments in nitrate content of vegetables (adjusted OR: 0.73, 95%CI: 0.55-0.97) and nitrate content of fruits (adjusted OR: 0.59, 95%CI: 0.36-0.97) was associated with reduced odds of NAFLD (P <  0.05). However, there was a positive association between each one SD increments in nitrate content of dairy products and meats and processed meats with odds of NAFLD (adjusted OR: 1.34, 95%CI: 1.03-1.74), (P <  0.05). CONCLUSION: Our finding suggested that a higher intake of vegetable nitrate may be related to a decrease the odds of NAFLD.

RORα contributes to the maintenance of genome ploidy in the liver of mice with diet-induced nonalcoholic steatohepatitis.

Hepatic polyploidization is closely linked to the progression of nonalcoholic fatty liver disease (NAFLD); however, the underlying molecular mechanism is not clearly understood. In this study, we demonstrated the role of retinoic acid-related orphan receptor α (RORα) in the maintenance of genomic integrity, particularly in the pathogenesis of NAFLD, using the high-fat diet (HFD)-fed liver-specific RORα knockout (RORα-LKO) mouse model. First, we observed that the loss of hepatic retinoic acid receptor-related orphan receptor α (RORα) accelerated hepatocyte nuclear polyploidization after HFD feeding. In 70% partial hepatectomy experiments, enrichment of hepatocyte polyploidy was more obvious in the RORα-LKO animals, which was accompanied by early progression to the S phase and blockade of the G2/M transition, suggesting a potential role of RORα in suppressing hepatocyte polyploidization in the regenerating liver. An analysis of a publicly available RNA sequencing (RNA-seq) and chromatin immunoprecipitation-seq dataset, together with the Search Tool of the Retrieval of Interacting Genes/Proteins database resource, revealed that DNA endoreplication was the top-enriched biological process Gene Ontology term. Furthermore, we found that E2f7 and E2f8, which encode key transcription factors for DNA endoreplication, were the downstream targets of RORα-induced transcriptional repression. Finally, we showed that the administration of JC1-40, an RORα activator (5 mg/kg body wt), significantly reduced hepatic nuclear polyploidization in the HFD-fed mice. Together, our observations suggest that the RORα-induced suppression of hepatic polyploidization may provide new insights into the pathological polyploidy of NAFLD and may contribute to the development of therapeutic strategies for the treatment of NAFLD.NEW & NOTEWORTHY It has been reported that hepatic polyploidization is closely linked to the progression of NAFLD. Here, we showed that the genetic depletion of hepatic RORα in mice accelerated hepatocyte polyploidization after high-fat diet feeding. The mechanism could be the RORα-mediated repression of E2f7 and E2f8, key transcription factors for DNA endoreplication. Thus, preservation of genome integrity by RORα could provide a new insight for developing therapeutics against the disease.

The Protective Role of 4-Acetylarylquinolinol B in Different Pathological Processes.

Antrodia cinnamomea is a traditional plant and a unique fungus native to Taiwan that has been reported to have many biological functions, including anti-inflammatory and anticancer activities. The compound 4-acetylarylquinolinol B (4-AAQB) is one of the main bioactive compounds in the stamens of Antrodia cinnamomea, and has many biological functions, such as anti-inflammatory, antiproliferative, blood sugar reduction, antimetastasis, and vascular tone relaxation. In recent years, the increasing evidences have shown that 4-AAQB is involved in many diseases; however, the relevant mechanisms have not been fully clarified. This review aimed to clarify the improvement by 4-AAQB in different pathological processes, as well as the compound's molecular mechanisms, in order to provide a theoretical reference for future related research.

The association between dietary inflammation scores and non-alcoholic fatty liver diseases in Iranian adults.

BACKGROUND: Potential dietary inflammation can precursor chronic diseases such as hepatic disorders. We aimed to examine the association of empirical dietary inflammatory patterns (EDIP) and dietary inflammation scores (DIS) with the risk of nonalcoholic fatty liver diseases (NAFLD) in Iranian adults. METHODS: This case-control study was conducted on 225 newly diagnosed NAFLD cases and 450 controls aged 20-60 years. The individuals' dietary data were collected using a validated food frequency questionnaire. The detection of NAFLD in subjects was done using the ultrasonography scan of the liver and confirmation of gastroenterologists. To calculate of EDIP score, the average daily intakes of each item (15 food items) were multiplied by the proposed weights, and then all the weighted values were summed. Also, to calculate the DIS score, each food item (18 food items) is multiplied by its specific weight to obtain the weighted values of each item. The weighted values were then standardized using the Z-score. Finally, the standardized weighted values of all the items were summed to get the overall DIS score for the individuals. Logistic regression models, adjusted for potential confounders, were used to estimate the odds ratios and 95% confidence interval (CI) of NAFLD across tertiles of EDIP and DIS. RESULTS: The mean (SD) age and BMI of the study population (53% male) were 38.1 (8.8) years and 26.8 (4.3) kg/m2, respectively. The median (IQR) of EDIP and DIS scores in individuals were 0.52 (0.34, 0.73), and 0.04 (- 0.55, 0.59), respectively. Based on the multivariable-adjusted model, after controlling for age, sex, physical activity, smoking, marital status, waist-to-hip ratio, and dietary energy intake, individuals in the second (OR 2.01, 95% CI 1.07-3.76) and third tertiles of DIS (OR 2.54, 95% CI 1.39-4.63) had a higher odds of NAFLD compared to the lowest tertile of DIS (Ptrend = 0.003). Also, in the final model, there is a significant direct association between EDIP score and odds of NAFLD [(OR T2 vs. T1 = 0.88, 95% CI 0.50-1.57) and (OR T3 vs. T1 = 1.82, 95% CI 1.02-3.23)], (Ptrend = 0.031). CONCLUSION: Our results suggested that higher scores of EDIP and DIS, indicating the high inflammatory potential of dietary pattern, are associated with increased odds of NAFLD in Iranian adults.

Effect of sour tea supplementation on liver enzymes, lipid profile, blood pressure, and antioxidant status in patients with non-alcoholic fatty liver disease: A double-blind randomized controlled clinical trial.

The aim of this study was to evaluate the efficacy of sour tea supplementation in patients with nonalcoholic fatty liver disease (NAFLD). Seventy NAFLD patients were enrolled in this randomized, double-blind, placebo-controlled clinical trial. Participants received sour tea in the form of a 450 mg capsule or a placebo capsule daily for 8 weeks. Anthropometric indices, liver enzymes, lipid profile, blood pressure, and antioxidant status were evaluated at the baseline and at the end of the study. Sixty-one participants completed the study. After 8 weeks, sour tea administration significantly decreased serum triglyceride (TG) (p = .03), alanine aminotransferase (ALT) (p = .01), and aspartate aminotransferase (AST) (p = .004) levels compared with the placebo. In addition, sour tea supplementation resulted in a significant reduction in systolic blood pressure (SBP) (p = .03) and diastolic blood pressure (DBP) (p = .04), and a significant increase in serum total antioxidant capacity (TAC) levels (p ˂ .001) compared with the placebo. However, no significant changes in anthropometric measures, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) levels were observed after sour tea supplementation compared with the placebo (p > .05). Sour tea supplementation may be effective in improving serum TG, liver enzymes, and blood pressure in patients diagnosed with NAFLD. Further studies are needed to address the exact mechanism of action of these effects.

Circadian rhythm-dependent induction of hepatic lipogenic gene expression in rats fed a high-sucrose diet.

Metabolic syndrome has become a global health challenge and was recently reported to be positively correlated with increased sucrose consumption. Mechanistic analyses of excess sucrose-induced progression of metabolic syndrome have been focused mainly on abnormal hepatic lipogenesis, and the exact contribution of excess sucrose to metabolic disorders remains controversial. Considering that carbohydrate and lipid metabolisms exhibit clear circadian rhythms, here we investigated the possible contribution of diurnal oscillations to responses of hepatic lipid metabolism to excess sucrose. We found that excess sucrose dose-dependently promotes fatty liver and hyperlipidemia in in rats fed a high-sucrose diet (HSD). We observed that excess sucrose enhances the oscillation amplitudes of the expression of clock genes along with the levels of hepatic lipid and carbohydrate metabolism-related mRNAs that increase lipogenesis. We did not observe similar changes in the levels of the transcription factors regulating the expression of these genes. This suggested that the excess sucrose-induced, circadian rhythm-dependent amplification of lipogenesis is post-transcriptionally regulated via the stability of metabolic gene transcripts. Of note, our findings also provide evidence that fructose causes some of the HSD-induced, circadian rhythm-dependent alterations in lipogenic gene expression. Our discovery of HSD-induced circadian rhythm-dependent alterations in lipogenesis at the post-transcriptional level may inform future studies investigating the complex relationships among sucrose uptake, circadian rhythm, and metabolic enzyme expression. Our findings could contribute to the design of chrono-nutritional interventions to prevent or manage the development of fatty liver and hyperlipidemia in sucrose-induced metabolic syndrome.

Co-Occurrence of Hepatitis A Infection and Chronic Liver Disease.

Hepatitis A virus (HAV) infection occasionally leads to a critical condition in patients with or without chronic liver diseases. Acute-on-chronic liver disease includes acute-on-chronic liver failure (ACLF) and non-ACLF. In this review, we searched the literature concerning the association between HAV infection and chronic liver diseases in PubMed. Chronic liver diseases, such as metabolic associated fatty liver disease and alcoholic liver disease, coinfection with other viruses, and host genetic factors may be associated with severe hepatitis A. It is important to understand these conditions and mechanisms. There may be no etiological correlation between liver failure and HAV infection, but there is an association between the level of chronic liver damage and the severity of acute-on-chronic liver disease. While the application of an HAV vaccination is important for preventing HAV infection, the development of antivirals against HAV may be important for preventing the development of ACLF with HAV infection as an acute insult. The latter is all the more urgent given that the lives of patients with HAV infection and a chronic liver disease of another etiology may be at immediate risk.

Relationships between severity of steatosis with glycemic control and carotid intima-media thickness among diabetic patients with ischemic heart disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become one of the major diseases plaguing worldwide. Several studies reported its association with ischemic heart disease (IHD). This study aims to determine the relationships between severity of steatosis with glycemic control and carotid intima-media thickness (CIMT) among a high-risk population of type 2 diabetes mellitus (T2DM) with proven IHD. MATERIALS AND METHODS: This was a cross-sectional study involving patients aged between 18 and 65 years diagnosed with T2DM with IHD (n = 150). Ultrasonography of the abdomen to determine NAFLD severity category and CIMT measurements was performed by two independent radiologists. NAFLD was graded according to the severity of steatosis (NAFLD-3, NAFLD-2, NAFLD-1, and NAFLD-0). Comparison between different stages of NAFLD (NAFLD-3, NAFLD-2, NAFLD-1, and NAFLD-0) was analyzed using Chi-square and analysis of variance tests for categorical and continuous variables, respectively. RESULTS: The prevalence of NAFLD was 71% (n = 107). NAFLD-1 was detected in 39% of the patients, 32% had NAFLD-2, no patients with NAFLD-3, and 29% had non-NAFLD. There were no patients with NAFLD-2 having higher systolic and diastolic blood pressure, weight, body mass index, waist circumference, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. Glycated hemoglobin (HbA1c) concentration was highest within the NAFLD-2. NAFLD-2 showed higher mean CIMT. Every 1% rise in HbA1c for patients with NAFLD significantly increases the CIMT by 0.03 mm (95% CI: 0.009, 0.052, P = 0.006). CONCLUSION: These findings suggest additional atherosclerotic risks within the NAFLD-2 group with significantly higher HbA1c and CIMT compared to the NAFLD-1 and NAFLD-0 groups. It is, therefore, vital to incorporate stricter glycemic control among patients with T2DM and IHD with moderate NAFLD as part of atherosclerotic risk management strategy.

Sfrp5 associates with beta-cell function in humans.

BACKGROUND: Secreted frizzled-related protein (Sfrp)5 improves insulin sensitivity, but impairs beta-cell function in rodents. However, the relationship between Sfrp5, insulin sensitivity and secretion in humans is currently unclear. Therefore, the aim of the study was to characterize the associations between serum Sfrp5 and indices of insulin sensitivity and beta-cell function from dynamic measurements using oral glucose tolerance tests (OGTT) in humans. MATERIAL AND METHODS: This study enrolled 194 individuals with nonalcoholic fatty liver disease (NAFLD), who were diagnosed based on ultrasound and liver transaminases and underwent a frequent sampling 75-g OGTT. Fasting serum Sfrp5 was measured by ELISA. Associations were assessed with several indices of insulin sensitivity and beta-cell function derived from glucose, insulin and C-peptide concentrations during the OGTT. RESULTS: Circulating Sfrp5 associated inversely with the insulinogenic index based on C-peptide (rs = -0·244, P = 0·001), but not with the insulinogenic index based on insulin levels (rs = -0·007, P = 0·926) after adjustment for age, sex and body mass index. Sfrp5 inversely correlated only with QUICKI as a marker of insulin sensitivity in the model adjusted for age and sex (rs = -0·149, P = 0·039). These associations were not influenced by the additional adjustment for hepatic steatosis index. CONCLUSIONS: The inverse association of serum Sfrp5 with beta-cell function suggests a detrimental role of Sfrp5 for insulin secretion also in humans. The severity of NAFLD does not appear to affect this relationship. The weak association between serum Sfrp5 and insulin sensitivity was partially explained by body mass.

Patented Farnesoid X receptor modulators: a review (2019 - present).

INTRODUCTION: The Farnesoid X receptor (FXR) is a key transcription factor that is involved in the bile acid signaling network. The modulation of the FXR activity influences glucose and lipid homeostasis, reduces obesity and insulin resistance, as well as it regulates the pathogenesis of inflammatory and metabolic disorders. FXR ligands have therefore emerged in drug discovery as promising therapeutic agents for the prevention and treatment of gastrointestinal and liver diseases, including cancer. AREAS COVERED: Recent advances in the field of FXR modulators are reviewed, with a particular attention on patent applications filed in the past 5 years related to both the discovery and development of FXR targeting drugs. EXPERT OPINION: FXR agonists have proven their efficacy and safety in humans and have shown a significant potential as clinical agents to treat metabolic and inflammatory associated conditions. However, several challenges, including adverse events such as pruritus, remain to be solved. Current studies aim to gain insights into the pathophysiological mechanisms by which FXR regulates metabolism and inflammation in terms of tissue/organ/isoform-specificity, post-translational modifications and coregulatory proteins, on the route of novel, improved FXR modulators.