Treatment Of Nonalcoholic Fatty Liver Disease Research Articles

Network Pharmacology and Molecular Docking Integrated with Molecular Dynamics Simulations Investigate the Pharmacological Mechanism of Yinchenhao Decoction in the Treatment of Non-alcoholic Fatty Liver Disease.

Non-Alcoholic Fatty Liver Disease (NAFLD) has become a significant health and economic burden globally. Yinchenhao decoction (YCHD) is a traditional Chinese medicine formula that has been validated to exert therapeutic effects on NAFLD. The current study aimed to explore the pharmacological mechanisms of YCHD on NAFLD and further identify the potential active compounds acting on the main targets. Compounds in YCHD were screened and collected from TCMSP and published studies, and their corresponding targets were obtained from the SWISS and SEA databases. NAFLD-related targets were searched in the GeneCards and DisGeNet databases. The "compound- intersection target" network was constructed to recognize the key compounds. Moreover, a PPI network was constructed to identify potential targets. GO and KEGG analyses were performed to enrich the functional information of the intersection targets. Then, molecular docking was used to identify the most promising compounds and targets. Finally, molecular dynamics (MD) simulations were performed to verify the binding affinity of the most potential compounds with the key targets. A total of 53 compounds and 556 corresponding drug targets were collected. Moreover, 2684 NAFLD-related targets were obtained, and 201 intersection targets were identified. Biological processes, including the apoptotic process, inflammatory response, xenobiotic metabolic process, and regulation of MAP kinase activity, were closely related to the treatment of NAFLD. Metabolic pathways, non-alcoholic fatty liver disease, the MAPK signaling pathway, and the PI3K-Akt signaling pathway were found to be the key pathways. Molecular docking showed that quercetin and isorhamnetin were the potential active compounds, while AKT1, IL1B, and PPARG were the most promising targets. MD simulations further verified that the binding of PPARG-isorhamnetin (-35.96 ± 1.64 kcal/mol) and AKT1-quercetin (-31.47 ± 1.49 kcal/mol) was due to their lowest binding free energy. This study demonstrated that YCHD exerts therapeutic effects for the treatment of NAFLD through multiple targets and pathways, providing a theoretical basis for further pharmacological research on the potential mechanisms of YCHD in NAFLD.

Survey of physicians' knowledge about pediatric nonalcoholic fatty liver disease in China.

To evaluate physicians' awareness and knowledge towards pediatric nonalcoholic fatty liver disease (NAFLD) and their attitude toward change in nomenclature from NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) in China. The questionnaire survey contained five parts (characteristics of the participants, epidemiology, diagnosis, management of NAFLD, and attitudes toward the nomenclature of MAFLD/MASLD). The participants included 53 hepatologists, 88 gastroenterologists (GEs), 74 endocrinologists (ENDOs), 61 primary care physicians (PCPs), and 157 pediatricians across 31 municipalities, provinces and autonomous regions of China's mainland. Hepatologists saw the largest number of pediatric NAFLD patients annually (median 9 [range 1-20]), with the lowest number by PCPs (even notwithstanding one patient annually). The primary sources of pediatric NAFLD knowledge were acquired via guidelines. Hepatologists had the highest total knowledge score among all five types of physicians. Approximately one-third of nonspecialists (ENDOs and PCPs) considered liver biopsy necessary for pediatric NAFLD patients, and this percentage increased to half in specialists (hepatologists and GEs). For nonspecialists, the major barriers to the management of pediatric NAFLD were poor patient adherence to lifestyle modifications and lacking confidence in managing NAFLD. Above 90% physicians agreed to change the nomenclature NAFLD to MAFLD; however, they were not sure whether it could reduce the economic burden. Despite the epidemic of pediatric NAFLD in China, a significant knowledge gap remains in the identification, diagnosis, and treatment of pediatric NAFLD, particularly among frontline workers such as pediatricians and PCPs. More education programs should be carried out in the future.

Treatment of NAFLD: Diet, Physical Activity, and Potential Pharmacological Options

Introduction and purpose Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and according to current data, it affects 38% of the global population. NAFLD includes non-alcoholic fatty liver and the progressive form called non-alcoholic steatohepatitis, which is characterized by damage, inflammation of hepatocytes, and fibrosis. NASH can lead to cirrhosis and hepatocellular carcinoma. Moreover, it increases the risk of diabetes mellitus type 2, lipid disorders, and death due to cardiovascular causes. Currently, no cure is aimed at reducing the severity of NALFD and liver fibrosis. The aim of this study was to provide a total review of the current state of knowledge regarding NAFLD treatment and to identify potential areas for further evaluation. Materials and method The PubMed and Google Scholar databases were thoroughly searched to select appropriate sources for this article. A brief description of the state of knowledge Diet, weight management, and physical activity constitute fundamental elements of every treatment regimen for NAFLD. Regarding pharmacological treatment, European guidelines recommend the use of vitamin E or pioglitazone in certain patients. Recently, the topic of NAFLD treatment has been a popular subject among scientists who are striving to discover new therapeutic options. A lot of recent research has exhibited promising outcomes for GLP-1 agonists, metformin, SGLT2 inhibitors, FXR, and PPAR ligands. Summary The findings of the conducted studies so far are encouraging and offer promise for novel pharmacological interventions in the treatment of NAFLD. Nonetheless, before implementation, further research in this area will be imperative to comprehensively evaluate the efficacy and safety profiles of these pharmaceuticals.

Treatment of NAFLD: Diet, Physical Activity, and Potential Pharmacological Options

Introduction and purpose Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and according to current data, it affects 38% of the global population. NAFLD includes non-alcoholic fatty liver and the progressive form called non-alcoholic steatohepatitis, which is characterized by damage, inflammation of hepatocytes, and fibrosis. NASH can lead to cirrhosis and hepatocellular carcinoma. Moreover, it increases the risk of diabetes mellitus type 2, lipid disorders, and death due to cardiovascular causes. Currently, no cure is aimed at reducing the severity of NALFD and liver fibrosis. The aim of this study was to provide a total review of the current state of knowledge regarding NAFLD treatment and to identify potential areas for further evaluation. Materials and method The PubMed and Google Scholar databases were thoroughly searched to select appropriate sources for this article. A brief description of the state of knowledge Diet, weight management, and physical activity constitute fundamental elements of every treatment regimen for NAFLD. Regarding pharmacological treatment, European guidelines recommend the use of vitamin E or pioglitazone in certain patients. Recently, the topic of NAFLD treatment has been a popular subject among scientists who are striving to discover new therapeutic options. A lot of recent research has exhibited promising outcomes for GLP-1 agonists, metformin, SGLT2 inhibitors, FXR, and PPAR ligands. Summary The findings of the conducted studies so far are encouraging and offer promise for novel pharmacological interventions in the treatment of NAFLD. Nonetheless, before implementation, further research in this area will be imperative to comprehensively evaluate the efficacy and safety profiles of these pharmaceuticals.

Research Progress of Chaihu Shugan San in the Treatment of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) belongs to the categories of "flank pain" and "liver fetish" in traditional Chinese medicine. The causes of NAFLD are complex, such as obesity, type 2 diabetes, hyperlipidemia, hypothyroidism, hypopituitarism, sleep apnea syndrome, polycystic ovary syndrome, sexual dysfunction, acanthosis nigricans, vitamin D deficiency and osteoporosis. The causes of NAFLD are very complex, such as obesity, type 2 diabetes. With the development of Chinese society and the further improvement of people's living standards in recent years, people's daily life, working style and diet structure have also changed. The incidence of NAFLD is increasing rapidly, and it has become a common disease in the world, posing a serious threat to our health and affecting our daily life. Traditional Chinese medicine emphasizes a holistic approach and treatment based on syndrome differentiation, with multiple channels, multiple aspects, multiple levels, multiple perspectives, and minimal side effects. It has a considerable therapeutic effect in the treatment of NAFLD. This article aims to organize and summarize the research literature on Chaihu Shugan San in the treatment of NAFLD in recent years, providing reference for further clinical research and application of Chaihu Shugan San in the treatment of NAFLD.

Research Progress of Chaihu Shugan San in the Treatment of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) belongs to the categories of "flank pain" and "liver fetish" in traditional Chinese medicine. The causes of NAFLD are complex, such as obesity, type 2 diabetes, hyperlipidemia, hypothyroidism, hypopituitarism, sleep apnea syndrome, polycystic ovary syndrome, sexual dysfunction, acanthosis nigricans, vitamin D deficiency and osteoporosis. The causes of NAFLD are very complex, such as obesity, type 2 diabetes. With the development of Chinese society and the further improvement of people's living standards in recent years, people's daily life, working style and diet structure have also changed. The incidence of NAFLD is increasing rapidly, and it has become a common disease in the world, posing a serious threat to our health and affecting our daily life. Traditional Chinese medicine emphasizes a holistic approach and treatment based on syndrome differentiation, with multiple channels, multiple aspects, multiple levels, multiple perspectives, and minimal side effects. It has a considerable therapeutic effect in the treatment of NAFLD. This article aims to organize and summarize the research literature on Chaihu Shugan San in the treatment of NAFLD in recent years, providing reference for further clinical research and application of Chaihu Shugan San in the treatment of NAFLD.

Non-alcoholic fatty liver disease increases the risk of biochemical recurrence in high-grade metastatic prostate cancer patients.

Non-alcoholic fatty liver disease (NAFLD) has been reported to be helpful to identify high-risk individuals of developing prostate cancer. Our aim is to investigate the relationship between NAFLD and biochemical recurrence in metastatic prostate cancer patients. We retrospectively investigated 602 patients with metastatic prostate cancer receiving the androgen deprivation therapy. Liver fat was estimated with liver-to-spleen ratio by computed tomography (CT) scans. The relationship between NAFLD and biochemical recurrence was investigated with Cox models. The model for biochemical recurrence was adjusted for multiple variables. NAFLD was significantly associated with biochemical recurrence in patients with Gleason score ≥4+3 when adjusting for each of body mass index (hazards ratio [HR]=1.38; 95% confidence interval [CI]=1.08-1.77; p=0.01), visceral adipose tissue (HR=1.36; 95% CI=1.07-1.74; p=0.01), hypertension (HR=1.41; 95% CI=1.10-1.80; p=0.01), and diabetes mellitus (HR=1.42; 95% CI=1.11-1.82; p=0.01), using age and prostate-specific antigen level as potential confounder. The 2-year biochemical recurrence rate in the Gleason score ≥4+3 patients with and without NAFLD was 84.0% (100/119) and 72.2% (130/180), respectively (p=0.018). The median biochemical recurrence free survival of the Gleason score ≥4+3 patients with and without NAFLD were 17 and 21 months, respectively (p=0.005). NAFLD is an independent risk factor for biochemical recurrence in patients with high-grade metastatic prostate cancer. If validated in prospective studies, future research should test whether treatment of NAFLD can lead to better prognosis.

A Mendelian randomization study: Years of education and nonalcoholic fatty liver disease.

Though years of education have been connected to nonalcoholic fatty liver disease (NAFLD), the exact mechanism underlying this linkage is still unknown. To investigate the causal association between years of education and NAFLD, we will use a 2-sample Mendelian randomization (MR) technique. : Genome-wide association studies data on years of education (n = 766,345) and genome-wide association studies data on nonaffiliated mental illness (n = 778,614) were screened for genetic variations as instrumental variables in the Mr-Base database. MR-Egger regression, weighted median, and inverse variance weighted were used in the MR analysis. Years of education (odds ratio = 0.63; 95% confidence interval: 0.47-0.79; P = 1.28 × 10-8) might be protective against the development of NAFLD. Among the sensitivity analyses were the following: the MR-Egger intercept test revealed P > .05, suggesting that there was no horizontal pleiotropy in the MR analysis and that the inverse variance weighted results were trustworthy; the Cochran Q test revealed P > .05, suggesting that there was no heterogeneity between the 2 samples; Funnel plot results demonstrated that there was no bias in the link between the measure of variability and the impact size. Leave-1-out analysis results demonstrated that no 1 single nucleotide polymorphism had a significant effect on the study's results, showing that the MR results were stable. This study has investigated the connection between years of education and NAFLD, offering novel suggestions for NAFLD treatment and prevention.

The role and mechanism of pyroptosis and potential therapeutic targets in non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease (NAFLD) is a clinical pathological syndrome characterized by the excessive accumulation of fat within liver cells, which can progress to end-stage liver disease in severe cases, posing a threat to life. Pyroptosis is a distinct, pro-inflammatory form of cell death, differing from traditional apoptosis. In recent years, there has been growing research interest in the association between pyroptosis and NAFLD, encompassing the mechanisms and functions of pyroptosis in the progression of NAFLD, as well as potential therapeutic targets. Controlled pyroptosis can activate immune cells, eliciting host immune responses to shield the body from harm. However, undue activation of pyroptosis may worsen inflammatory responses, induce cellular or tissue damage, disrupt immune responses, and potentially impact liver function. This review elucidates the involvement of pyroptosis and key molecular players, including NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome, gasdermin D (GSDMD), and the caspase family, in the pathogenesis and progression of NAFLD. It emphasizes the promising prospects of targeting pyroptosis as a therapeutic approach for NAFLD and offers valuable insights into future directions in the field of NAFLD treatment.

The efficacy and safety of Dachaihu decoction in the treatment of nonalcoholic fatty liver disease: a systematic review and meta-analysis.

Nonalcoholic fatty liver disease (NAFLD), also known as metabolic associated fatty liver disease (MAFLD), is a common liver condition characterized by excessive fat accumulation in the liver which is not caused by alcohol. The main causes of NAFLD are obesity and insulin resistance. Dachaihu decoction (DCHD), a classic formula in traditional Chinese medicine, has been proved to treat NAFLD by targeting different aspects of pathogenesis and is being progressively used in the treatment of NAFLD. DCHD is commonly applied in a modified form to treat the NAFLD. In light of this, it is imperative to conduct a systematic review and meta-analysis to assess the effectiveness and safety of DCHD in the management of NAFLD. There is a need for a systematic review and meta-analysis to assess the effectiveness and safety of modified DCHD in treating NAFLD. The objective of this meta-analysis was to systematically assess the clinical effectiveness and safety of DCHD in treating NAFLD. This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Including seven databases, both Chinese and English databases were searched for relevant studies. The quality of included studies was carefully assessed using the bias risk assessment tool in the Cochrane Handbook. Eligible articles were the source of extracted data which was meta-analyzed by using Review Manager 5.4 and Stata 17.0. A total of 10 studies containing 825 patients were included. Compared with conventional treatments, combined treatment could clearly improve the liver function of NAFLD patients, which could reduce the levels of ALT (MD = -7.69 U/L, 95% CI: -11.88 to -3.51, p < 0.001), AST (MD = -9.58 U/L, 95% CI: -12.84 to -6.33, p < 0.01), and it also had a certain impact on regulating lipid metabolism, which could reduce the levels of TC (MD = -0.85 mmol/L, 95% CI: -1.22 to 0.48, p < 0.01), TG (MD = -0.45 mmol/L, 95% CI: -0.64 to 0.21, p < 0.01). Adverse event showed that DCHD was relatively safe. Due to the inclusion of less than 10 trials in each group, it was not possible to conduct a thorough analysis of publication bias. According to the meta-analysis, in the treatment of the NAFLD, it is clear that the combination of DCHD was advantages over conventional treatment alone in improving liver function, regulating lipid metabolism. Additionally, DCHD demonstrates a relatively safe profile. Nevertheless, due to limitations in the quality and quantity of the studies incorporated, the effectiveness and safety of DCHD remain inconclusive. Consequently, further high-quality research is imperative to furnish more substantial evidence supporting the widespread clinical application of DCHD. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023397353, CRD42023397353.

A PNPLA3-Deficient iPSC-Derived Hepatocyte Screen Identifies Pathways to Potentially Reduce Steatosis in Metabolic Dysfunction-Associated Fatty Liver Disease.

The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3-/- and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells.

Silibinin Targeting Heat Shock Protein 90 Represents a Novel Approach to Alleviate Nonalcoholic Fatty Liver Disease by Simultaneously Lowering Hepatic Lipotoxicity and Enhancing Gut Barrier Function.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological condition characterized by intrahepatic ectopic steatosis. Due to the increase in high-calorie diets and sedentary lifestyles, NAFLD has surpassed viral hepatitis and become the most prevalent chronic liver disease globally. Silibinin, a natural compound, has shown promising therapeutic potential for the treatment of liver diseases. Nevertheless, the ameliorative effects of silibinin on NAFLD have not been completely understood, and the underlying mechanism is elusive. Therefore, in this study, we used high-fat diet (HFD)-induced mice and free fatty acid (FFA)-stimulated HepG2 cells to investigate the efficacy of silibinin for the treatment of NAFLD and elucidate the underlying mechanisms. In vivo, silibinin showed significant efficacy in inhibiting adiposity, improving lipid profile levels, ameliorating hepatic histological aberrations, healing the intestinal epithelium, and restoring gut microbiota compositions. Furthermore, in vitro, silibinin effectively inhibited FFA-induced lipid accumulation in HepG2 cells. Mechanistically, we reveal that silibinin possesses the ability to ameliorate hepatic lipotoxicity by suppressing the heat shock protein 90 (Hsp90)/peroxisome proliferator-activated receptor-γ (PPARγ) pathway and alleviating gut dysfunction by inhibiting the Hsp90/NOD-like receptor pyrin domain-containing 3 (NLRP3) pathway. Altogether, our findings provide evidence that silibinin is a promising candidate for alleviating the "multiple-hit" in the progression of NAFLD.

Interpretation of the 2024 American Diabetes Association guidelines for the comprehensive management of non-alcoholic fatty liver disease combined with diabetes mellitus

Non-alcoholic fatty liver disease (NAFLD) is a common concomitant disease in adults with type 2 diabetes mellitus (T2DM) and prediabetes. Therefore, T2DM/NAFLD patient populations are at high risk for cardiovascular disease. The occurrence and progression of non-alcoholic fatty liver disease-related liver fibrosis and cardiovascular disease have a severe impact on the patient's prognosis and mortality rate. The American Diabetes Association's 2024 "Guidelines for the Standardized Management of Diabetes" put forward recommendations relevant to the screening, evaluation, treatment, and management of NAFLD in T2DM and prediabetic populations, as well as liver fibrosis. The important measures for decelerating liver inflammation and fibrosis progression and the risk of cardiovascular disease are based on improvements in lifestyle methods, weight loss, and blood sugar control.

Non-alcoholic fatty liver disease in type 2 diabetes: Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies.

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, affecting more than half of the people living with type 2 diabetes (T2D). The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other, which significantly increases the hepatic as well as extrahepatic complications. Until recently, there was no approved pharmacological treatment for NAFLD/ nonalcoholic steatohepatitits (NASH). However, there is evidence that drugs used for diabetes may have beneficial effects on NAFLD. Insulin sensitizers acting through peroxisome proliferator-activated receptor (PPAR) modulation act on multiple levels of NAFLD pathogenesis. Pioglitazone (PPARγ agonist) and saroglitazar (PPARα/γ agonist) are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D, although data on biopsy-proven NASH are lacking with the latter. Initial data on elafibanor (PPAR α/δ agonist) and Lanifibranor (pan PPAR agonist) are promising. On the other hand, incretin therapies based on glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and dual- and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties. GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual- and triple-agonists are required. Furthermore, the long-term safety of these therapies in NAFLD needs to be established. Collaborative efforts among healthcare providers such as primary care doctors, hepatologists, and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic SIRT1/PGC-1α pathway

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide in recent years, causing severe economic and social burdens. Therefore, the lack of currently approved drugs for anti-NAFLD has gradually gained attention. SIRT1, as a member of the sirtuins family, is now the most widely studied in the pathophysiology of many metabolic diseases, and has great potential for preventing and treating NAFLD. Natural products such as Diosgenin (DG) have the potential to be developed as clinical drugs for the treatment of NAFLD due to their excellent multi-target therapeutic effects. In this study, we found that DG can activate the SIRT1/PGC-1α pathway and upregulate the expression of its downstream targets nuclear respiratory factor 1 (NRF1), complex IV (COX IV), mitofusin-2 (MFN2), and PPARα (perox-isome proliferator-activated receptor α) in SD rats induced by high-fat diet (HFD) and HepG2 cells caused by free fatty acids (FFAs, sodium oleate: sodium palmitate = 2:1). Conversely, the levels of dynamin-related protein 1 (DRP1) and inflammatory factors, including NF-κB p65, IL6, and TNFα, were downregulated both in vitro and in vivo. This improved mitochondrial dysfunction, fatty acid oxidation (FAO), lipid accumulation, steatosis, oxidative stress, and hepatocyte inflammation. Subsequently, we applied SIRT1 inhibitor EX527 and SIRT1 agonist SRT1720 to confirm further the necessity of activating SIRT1 for DG to exert therapeutic effects on NAFLD. In summary, these results further demonstrate the potential therapeutic role of DG as a SIRT1 natural agonist for NAFLD. (Graphical Abstracts)

Coprococcus protects against high-fat diet-induced nonalcoholic fatty liver disease in mice.

The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing annually, leading to substantial medical and health burdens. Numerous studies have demonstrated the potential effectiveness of intestinal probiotics as a treatment strategy for NAFLD. Therefore, the objective of this study is to identify a probiotic for the treatment of NAFLD. In this study, blood and fecal samples were collected from 41 healthy volunteers and 44 patients diagnosed with NAFLD. Analysis of the 16S rDNA sequencing data and quantitative real-time PCR (RT-qPCR) revealed a significant reduction in the abundance of Coprococcus in NAFLD patients. Subsequent animal experiments demonstrated that Coprococcus was able to effectively reverse liver lipid accumulation, inflammation, and fibrosis induced by a high-fat diet (HFD) in mice. This study provides the first in vivo evidence that Coprococcus is a beneficial bacterium capable of preventing NAFLD and has the same probiotic effect in mice as Lactobacillus GG (LGG), a positive control. Therefore, Coprococcus has the potential to serve as a probiotic for the prevention and treatment of NAFLD in humans.

Design, synthesis, and biological evaluation of (E)-3-(3-methoxy-4-substituted phenyl)-acrylic acid derivatives: Role of compound S17 in regulating lipid accumulation via AMPK activation

Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a global public health concern characterized by excessive lipid accumulation in the liver. Ferulic acid (FA), a common foodborne phenolic acid, has been shown to reduce lipid accumulation by activating adenosine monophosphate-activated protein kinase (AMPK) and suppressing the expression of sterol regulatory element-binding protein-1 (SREBP-1). In this study, we synthesized a new class of (E)-3-(3-methoxy-4-substituted phenyl)-acrylic acid derivatives as AMPK activators. Among these derivatives, compound S17 demonstrated a more potent inhibitory effect on lipid accumulation compared to its counterparts. Specifically, S17 notably diminished intracellular triglyceride (TG) levels and the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which are indicators of liver function. In addition, S17 curtailed intracellular lipid accumulation by activating the AMPK signaling pathway and down-regulating the protein expression of SREBP-1 in free fatty acid (FFA)-induced HepG2 cells. Therefore, findings from this study strongly suggest that compound S17 may serve as a promising therapeutic candidate for the treatment of NAFLD.

Non-alcoholic fatty liver disease: pathogenesis and assessing the impact of dietary bioactive compounds on the liver

Non-alcoholic fatty liver disease (NAFLD) is a pathological condition ranging from simple steatosis to non-alcoholic steatohepatitis, cirrhosis, and liver cancer. NAFLD is a complex disease mediated by metabolic, environmental, and genetic mechanisms. Many factors such as insulin resistance, lipotoxicity, inflammation, mitochondrial dysfunction, endoplasmic reticulum stress, circadian rhythm, genetics, epigenetics, dietary factors, and gut microbiota play a crucial role in the pathogenesis of NAFLD. Lifestyle changes such as healthy diet, physical activity, avoiding alcohol and smoking are involved in the NAFLD treatment. Dietary bioactive compounds including curcumin, resveratrol, catechins, quercetin, sulforaphane, epigallocatechin-3-gallate, alkaloids, vitamins, and peptides have many health promoting effects such as antioxidant, anti-inflammatory, antihypertensive, chemopreventive, and hepatoprotective. In this review, the pathophysiology of NAFLD and the effects of dietary bioactive compounds on this disease will be discussed in detail with updated information.

Identifying potential drug targets for non-alcoholic fatty liver disease: a drug target Mendelian randomization study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UK Research and Innovation Training Grant: Centre for Doctoral Training in AI-enabled Healthcare Systems Background Non-alcoholic fatty liver disease (NAFLD), a range of conditions caused by the build-up of fat in the liver, is the most common form of chronic liver disease, with an estimated prevalence of ~25% globally. NAFLD is associated with increased risk of all-cause mortality, with CVD emerging as the primary cause of death amongst affected individuals. The aetiology of NAFLD is not yet clearly understood, and currently no drugs exist for its treatment, with therapeutics aimed at symptom management instead. Purpose To identify and prioritise candidate protein drug targets and pathways relevant for therapeutic intervention in NAFLD. Methods To identify plasma proteins causally associated with NAFLD, we analysed genetic associations on 1,561 proteins from 35,559 participants in the deCODE study, and compared these to associations from a GWAS of biopsy confirmed NAFLD cases (1,483 cases, 17,781 controls). We sourced genetic variants from a 400kbp region around each protein-coding gene, pruning variants on an F-statistic of 15, minor allele frequency threshold of 1% and linkage disequilibrium r-squared of 0.4. cis-Mendelian randomization (MR) was used to identify proteins associated with NAFLD. Bias due to pleiotropy was limited by excluding variants with leverage statistic more than 3 times the mean, or outlier statistic larger than 10.83. We used colocalization analysis to identify proteins with a posterior probability of at least 0.8, indicating the presence of common causal variants. We further prioritised proteins by annotating them with information on druggability (i.e. whether a protein is a target for a known drug, or predicted to be a target for a drug), mRNA expression in pathology-relevant tissues, and involvement in known biological pathways. Results We identified 5 proteins with a multiplicity-corrected (p&amp;lt;3.2×10-5) association with NAFLD, and strong evidence of genetic colocalization: CYB5A, NT5C, NCAN, TGFBI, DAPK2. TGFBI and DAPK2 are potentially druggable, with all five found to be expressed in both liver and adipose tissues. Pathway analysis indicated the involvement of NT5C, CYB5A, NCAN in Reactome pathway R-HSA-1430728 reflecting cellular energy metabolism, including mitochondrial lipid metabolism, which is strongly implicated with NAFLD. Conclusion We identified a prioritised set of five plasma proteins influencing NAFLD, including druggable proteins informing de novo and ongoing drug development programs. Figure: MR effect estimates of proteins on NAFLD A: Effect of each protein on NAFLD. Each point represents a protein, effect estimates are reported in log(odds ratio) and statistical significance in -log(p-value). Coloured points represent proteins passing the multiplicity-corrected p-value threshold B: MR effect estimates of prioritised proteins. Estimates are reported in log(odds ratio). Proteins are annotated according to their druggability based on the British National Formulary and ChEMBL

Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) poses a significant health challenge in modern societies due to shifts in lifestyle and dietary habits. Its complexity stems from genetic predisposition, environmental influences, and metabolic factors. Epigenetic processes govern various cellular functions such as transcription, chromatin structure, and cell division. In NAFLD, these epigenetic tendencies, especially the process of histone methylation, are intricately intertwined with fat accumulation in the liver. Histone methylation is regulated by different enzymes like methyltransferases and demethylases and influences the expression of genes related to adipogenesis. While early-stage NAFLD is reversible, its progression to severe stages becomes almost irreversible. Therefore, early detection and intervention in NAFLD are crucial, and understanding the precise role of histone methylation in the early stages of NAFLD could be vital in halting or potentially reversing the progression of this disease.