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.

Yao-Shan of traditional Chinese medicine: an old story for metabolic health.

Type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), cardio-cerebrovascular diseases (CCVDs), hyperuricemia and gout, and metabolic-related sexual dysfunction are metabolic diseases that affect human health in modern society. Scientists have made great efforts to investigate metabolic diseases using cell models in vitro or animal models in the past. However, the findings from cells or animals are difficult to translate into clinical applications due to factors such as the in vitro and in vivo differences; the differences in anatomy, physiology, and genetics between humans and animals; and the differences in microbiome-host interaction. The Chinese have extensively used the medicated diet of traditional Chinese medicine (TCM) (also named as Yao-Shan of TCM, Chinese Yao-Shan et al.) to maintain or improve cardiometabolic health for more than 2,200 years. These ancient classic diets of TCM are essential summaries of long-term life and clinical practices. Over the past 5 years, our group has made every effort to collect and sort out the classic Yao-Shan of TCM from the ancient TCM literature since Spring and Autumn and Warring States Period, especially these are involved in the prevention and treatment of metabolic diseases, such as diabetes, NAFLD, CCVDs, hyperuricemia and gout, and sexual dysfunction. Here, we summarized and discussed the classic Yao-Shan of TCM for metabolic diseases according to the time recorded in the ancient literature, and revised the Latin names of the raw materials in these Yao-Shan of TCM. Moreover, the modern medicine evidences of some Yao-Shan of TCM on metabolic diseases have also been summarized and emphasized in here. However, the exact composition (in terms of ratios), preparation process, and dosage of many Yao-Shan are not standardized, and their main active ingredients are vague. Uncovering the mystery of Yao-Shan of TCM through modern biological and chemical strategies will help us open a door, which is ancient but now looks new, to modulate metabolic homeostasis and diseases.

We are what we eat: The role of lipids in metabolic diseases.

Lipids play a fundamental role, both structurally and functionally, for the correct functioning of the organism. In the last two decades, they have evolved from molecules involved only in energy storage to compounds that play an important role as components of cell membranes and signaling molecules that regulate cell homeostasis. For this reason, their interest as compounds involved in human health has been gaining weight. Indeed, lipids derived from dietary sources and endogenous biosynthesis are relevant for the pathophysiology of numerous diseases. There exist pathological conditions that are characterized by alterations in lipid metabolism. This is particularly true for metabolic diseases, such as liver steatosis, type 2 diabetes, cancer and cardiovascular diseases. The main issue to be considered is lipid homeostasis. A precise control of fat homeostasis is required for a correct regulation of metabolic pathways and safe and efficient energy storage in adipocytes. When this fails, a deregulation occurs in the maintenance of systemic metabolism. This happens because an increased concentrations of lipids impair cellular homeostasis and disrupt tissue function, giving rise to lipotoxicity. Fat accumulation results in many alterations in the physiology of the affected organs, mainly in metabolic tissues. These alterations include the activation of oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, increased inflammation, accumulation of bioactive molecules and modification of gene expression. In this chapter, we review the main metabolic diseases in which alterations in lipid homeostasis are involved and discuss their pathogenic mechanisms.

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.

A Healthful Plant-Based Diet Is Associated with Lower Odds of Nonalcoholic Fatty Liver Disease.

There is little evidence for the associations of the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI) with the odds of nonalcoholic fatty liver disease (NAFLD). We present a nationwide cross-sectional study among US adults aged 18 years or older. Diet was assessed by 24-h recalls. Overall PDI, hPDI, and uPDI were constructed based on 18 food groups. NAFLD was defined based on controlled attenuation parameter derived via transient elastography (TE) in the absence of other causes of chronic liver disease. Among 3900 participants with eligible TE examination, 1686 were diagnosed with NAFLD. The overall PDI was not associated with NAFLD prevalence (comparing extreme tertiles of PDI score OR = 1.03, 95% CI 0.76, 1.38, ptrend = 0.609). However, hPDI was inversely (OR = 0.50, 95% CI 0.35, 0.72, ptrend < 0.001), while uPDI was positively associated with odds of NAFLD (OR = 1.37, 95% CI 0.93, 2.02, ptrend = 0.009) in the multivariable-adjusted models without body mass index (BMI). After further adjustment for BMI, only the association of hPDI with NAFLD remained statistically significant (OR = 0.64, 95% CI 0.46, 0.87, ptrend = 0.006). Such inverse association appeared stronger in non-Hispanic whites, but not in other racial/ethnic groups (pinteraction = 0.009). Our findings suggest that a plant-based diet rich in healthy plant foods might be associated with lower odds of NAFLD, particularly among US non-Hispanic whites. Clinical trials and cohort studies to validate our findings are needed.

Non-alcoholic fatty liver disease and dairy products consumption: Results from FASA Persian cohort study.

Background/objectives: There are limited data on the association between dairy products consumption and nonalcoholic fatty liver disease (NAFLD). This study was conducted to evaluate the association between total intake of different dairy products and fatty liver index (FLI), a marker of subclinical fatty liver. Methods: A total of 7,540 adults were included in this population-based cohort study. Dairy products consumption was evaluated by a validated interview questionnaire for food intake frequency. The FLI was calculated using the standard formula. Liver enzyme levels, lipid profiles, glycemic profiles and demographic characteristics were recorded for all participants. Univariate and multiple logistic regression models were used to respectively assess the mean percentage difference of mean FLI and odds ratios (ORs) for subclinical NAFLD across quantiles of dairy consumption. Results: The mean age of all participants was 48.81 ± 9.631 years. FLI measurements for men and women were 26.71 ± 23.39 and 39.99 ± 26.64 respectively, which was significantly higher in women (P < 0.05). Multiple logistic regression analysis demonstrated that the amount of milk consumption was an independent preventive predictor of FLI (OR = 0.96; 95% CI: 0.94-0.99), conversely, it did not predict higher levels of liver enzymes. In term of cheese intake, participants in the third tertile of cheese intake had significantly lower FLI than lower tertiles (P = 0.01). However, there wasn't any significant association between cheese intake and the odds of FLI in the multivariate model (P > 0.05). We didn't find any significant association between yogurt consumption and NAFLD indicators (P > 0.05). Conclusion: Higher milk consumption was inversely associated with FLI. However, there wasn't any significant association between other types of dairy products and NAFLD indicators.

Non-alcoholic fatty liver disease and sarcopenia is associated with the risk of albuminuria independent of insulin resistance, and obesity.

BACKGROUND: Although non-alcoholic fatty liver disease (NAFLD) is associated with metabolic disorders, its influence on albuminuria has not been determined. The aim of this study was to identify the relationship between NAFLD and albuminuria in the general Korean population. METHODS: Data from the Korea National Health and Nutrition Examination Surveys (KNHANES) of 2008-2011 were analyzed (n = 1795). Albuminuria was defined as an albumin-to-creatinine ratio of ≥30 mg/g in random spot urine samples. NAFLD was defined as a fatty liver index (FLI) ≥60 or NAFLD liver fat score (LFS) > -0.64. RESULTS: A total of 289 (16.1 %) subjects were classified as having albuminuria. Subjects with NAFLD exhibited a higher rate of albuminuria than subjects without NAFLD (crude odds ratios [ORs] = 2.60-2.95, all P < 0.001). Regardless of hypertension, insulin resistance, or obesity, the risk for albuminuria was higher in the NAFLD group than in the group without NAFLD (measured by either FLI or LFS; all P < 0.001). When subjects with NAFLD had sarcopenia, the risk of albuminuria further increased (OR = 4.33-4.64, all P < 0.001). Multiple logistic regression analyses also demonstrated that NAFLD was independently associated with albuminuria (OR = 2.58, 95 % confidence interval [CI] = 1.66-4.02, P < 0.001 for FLI, OR = 1.87, 95 % CI = 1.28-2.75, P = 0.001 for LFS). CONCLUSIONS: NAFLD was associated with an increased risk of albuminuria in the general Korean population. This association was independent of hypertension, insulin resistance, chronic kidney disease, diabetes and obesity, and stronger in subjects with sarcopenia.

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.

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.

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.

LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia.

PURPOSE: To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. METHODS: A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. RESULTS: Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. CONCLUSIONS: In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT03466203.

Pharmacokinetics of Tropifexor, a Potent Farnesoid X Receptor Agonist, in Participants With Varying Degrees of Hepatic Impairment.

Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's pharmacokinetics, safety, and tolerability following a 200-µg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percentage free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUCinf,u ]) and a 1.3-fold increase in maximal exposure (Cmax,u ) vs those with normal hepatic function (geometric mean ratio: AUCinf,u , 1.64 [90%CI, 1.25-2.16]; Cmax,u , 1.30 [90%CI, 0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUCinf,u (1.61 [90%CI, 1.04-2.49]) and comparable Cmax,u (1.02 [90%CI, 0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment.

The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, followed by cholangiocarcinoma (CCA). HCC is the third most common cause of cancer death worldwide, and its incidence is rising, associated with an increased prevalence of obesity and nonalcoholic fatty liver disease (NAFLD). However, current treatment options are limited. Genetic factors and epigenetic factors, influenced by age and environment, significantly impact the initiation and progression of NAFLD-related HCC. In addition, both transcriptional factors and post-transcriptional modification are critically important for the development of HCC in the fatty liver under inflammatory and fibrotic conditions. The early diagnosis of liver cancer predicts curative treatment and longer survival. However, clinical HCC cases are commonly found in a very late stage due to the asymptomatic nature of the early stage of NAFLD-related HCC. The development of diagnostic methods and novel biomarkers, as well as the combined evaluation algorithm and artificial intelligence, support the early and precise diagnosis of NAFLD-related HCC, and timely monitoring during its progression. Treatment options for HCC and NAFLD-related HCC include immunotherapy, CAR T cell therapy, peptide treatment, bariatric surgery, anti-fibrotic treatment, and so on. Overall, the incidence of NAFLD-related HCC is increasing, and a better understanding of the underlying mechanism implicated in the progression of NAFLD-related HCC is essential for improving treatment and prognosis.

Role of dietary calcium and its possible mechanism against metabolic disorders: A concise review.

The global prevalence of metabolic disorders including hypertension, dyslipidemia, insulin resistance, nonalcoholic fatty liver, and cardiovascular diseases seemed to affect people of all ages cutting across the national, economic, and demographic barrier. Therefore, the prevention of metabolic disorders is considered of paramount importance. The dietary role of nutrients including vitamins and minerals is one of the recommended preventive measures against metabolic disorders in modern society. Recently, dietary calcium, a common nutrient not only showed a beneficial effect against obesity through weight management, but also gained great attention against the risk of metabolic disorders. Though dietary calcium shows several beneficial effects against metabolic disorders but some inconsistent results were also reported. So, the present review aims to extract recent knowledge as well as their possible underlying mechanisms regarding the role of dietary calcium against metabolic disorders. The present review also discusses the negative impact as well as prospect of calcium intake on health issues. In summary, high calcium diet prevents the harmful consequences of metabolic disorders by regulating hormonal actions, alteration in intracellular calcium level, renin-angiotensin system, intestinal fat absorption, fecal fat excretion, lipid metabolism, carbohydrate metabolism, inflammation, and oxidative stress which together improve the metabolic health of an individual. PRACTICAL APPLICATIONS: Metabolic disorder is a global health issue across all sections of society and is growing rapidly in spite of several attempts by the scientific community to prevent it. Recently dietary calcium gained great attention in the last few years for its role in the management and treatment of metabolic disorders. The current review highlights the beneficial role of dietary calcium against several metabolic complications by exploring their underlying mechanisms at cellular level. This study will provide valuable information regarding the recommendation of dietary calcium in health policy as well as its inclusion in the dietary chart through calcium-rich foods and/or taking calcium supplements which can be a useful approach in preventing the risk of metabolic disorder depending on the health status of an individual.

High sucrose diet-induced dysbiosis of gut microbiota promotes fatty liver and hyperlipidemia in rats.

Excess sucrose intake has been found to be a major factor in the development of metabolic syndrome, especially in promoting nonalcoholic fatty liver disease. The excess fructose is believed to targets the liver to promote de novo lipogenesis, as described in major biochemistry textbooks. On the contrary, in this study, we explored the possible involvement of gut microbiota in excess sucrose-induced lipid metabolic disorders, to validate a novel mechanism by which excess sucrose causes hepatic lipid metabolic disorders via alterations to the gut microbial community structure. Wistar male rats were fed either a control starch diet or a high-sucrose diet for 4 weeks. Half of the rats in each group were treated with an antibiotic cocktail delivered via drinking water for the entire experimental period. After 4 weeks, rats fed with the high-sucrose diet showed symptoms of fatty liver and hyperlipidemia. The architecture of cecal microbiota was altered in rats fed with high-sucrose diet as compared to the control group, with traits including increased ratios of the phyla Bacteroidetes/Firmicutes, reduced α-diversity, and diurnal oscillations changes. Antibiotic administration rescued high-sucrose diet-induced lipid accumulation in the both blood and liver. Levels of two microbial metabolites, formate and butyrate, were reduced in rats fed with the high-sucrose diet. These volatile short-chain fatty acids might be responsible for the sucrose-induced fatty liver and hyperlipidemia. Our results indicate that changes in the gut microbiota induced by a high-sucrose diet would promote the development of nonalcoholic fatty liver disease via its metabolites, such as short-chain fatty acids.

Exercise improves lipid droplet metabolism disorder through activation of AMPK-mediated lipophagy in NAFLD.

AIM: To emphasize the mechanism of the effect of exercise on lipid droplet (LD) metabolism disorder in nonalcoholic fatty liver disease (NAFLD). MAIN METHODS: C57BL/6J mice were randomly divided into three groups: The first group was fed with a normal diet (CON), the second group was fed a high-fat diet (HF), and finally group with a high-fat diet intervention and swim training (HF-EX). The total intervention period was 16 weeks. RT-PCR and Western blot were performed to evaluate the effect of exercise on LDs metabolism and the AMPK pathway. Histopathological examinations and immunofluorescence were performed to evaluate the lipid deposition and lipophagy in the liver. KEY FINDINGS: Exercise reduced liver steatosis and insulin resistance along with the stimulation of AMPK/SIRT1 signaling and downstream regulation of lipid metabolism. In addition, exercise increased the expression of autophagy marker and colocalization of LC3 and LAMP1 with LDs. SIGNIFICANCE: Exercise stimulated AMPK/SIRT1 and activated lipophagy in NAFLD. Enhancing lipophagy may be one of the key mechanisms of regulation and resolution of NAFLD by exercise.

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.

The effect of adiponectin in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the potential role of polyphenols in the modulation of adiponectin signaling.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, as it affects up to 30 % of adults in Western countries. Moreover, NAFLD is also considered an independent risk factor for cardiovascular diseases. Insulin resistance and inflammation have been identified as key factors in the pathophysiology of NAFLD. Although the mechanisms associated with the development of NAFLD remain to be fully elucidated, a complex interaction between adipokines and cytokines appear to play a crucial role in the development of this condition. Adiponectin is the most common adipokine known to be inversely linked with insulin resistance, lipid accumulation, inflammation and NAFLD. Consequently, the focus has been on the use of new therapies that may enhance hepatic expression of adiponectin downstream targets or increase the serum levels of adiponectin in the treatment NAFLD. While currently used therapies show limited efficacy in this aspect, accumulating evidence suggest that various dietary polyphenols may stimulate adiponectin levels, offering potential protection against the development of insulin resistance, inflammation and NAFLD as well as associated conditions of metabolic syndrome. As such, this review provides a better understanding of the role polyphenols play in modulating adiponectin signaling to protect against NAFLD. A brief discussion on the regulation of adiponectin during disease pathophysiology is also covered to underscore the potential protective effects of polyphenols against NAFLD. Some of the prominent polyphenols described in the manuscript include aspalathin, berberine, catechins, chlorogenic acid, curcumin, genistein, piperine, quercetin, and resveratrol.

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.