Mediating effect of diabetes on the relationship between nonalcoholic fatty liver disease and atherosclerotic cardiovascular disease: a prospective cohort study.

OBJECTIVE: This study explored the mediating effect of diabetes on the relationship between nonalcoholic fatty liver disease (NAFLD) and atherosclerotic cardiovascular disease (ASCVD). METHODS: In this prospective community cohort study, 82 975 participants were enrolled, with the primary outcome being the incidence of new-onset ASCVD. Using the Cox proportional hazards model, the hazard ratio (HR) and 95% confidence interval (CI) for ASCVD occurrence were computed between NAFLD and non-NAFLD groups. The correlation between NAFLD and diabetes was assessed using a binary logistic regression model, and that between NAFLD, diabetes and ASCVD using a mediation model. RESULTS: During follow-up, 9471 ASCVD cases were observed. Compared with individuals without NAFLD, those with NAFLD showed an increased ASCVD risk (HR: 1.424; 95% CI: 1.363-1.488; P < 0.001). Stratifying NAFLD based on metabolic subphenotypes revealed a higher ASCVD risk in the NAFLD combined with diabetes subgroup than in the non-NAFLD subgroup (HR: 1.960; 95% CI: 1.817-2.115; P < 0.001). NAFLD was positively associated with baseline diabetes (odds ratio: 2.983; 95% CI: 2.813-3.163; P < 0.001). Furthermore, NAFLD severity was positively correlated with diabetes risk. Mediation analysis indicated that diabetes partially mediated the effect of NAFLD on ASCVD incidence, accounting for 20.33% of the total effect. CONCLUSION: NAFLD is an independent predictor of increased ASCVD risk, which may be slightly mediated by diabetes in patients with NAFLD. Evaluating NAFLD and diabetes may be crucial in the early screening and prevention of ASCVD.

A male mouse model for metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma.

The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Here, we develop a mouse model (Streptozotocin with high-fat diet, STZ + HFD) that gradually develops fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. The hepatic transcriptomic features of STZ + HFD mice closely reflect those of patients with obesity accompanying type 2 diabetes mellitus, MASH, and MASLD-related HCC. Dietary changes and tirzepatide administration alleviate MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ + HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients is successfully established.

Unveiling metabolic dysfunction-associated fatty liver disease: Knowledge gaps and attitudes among Lebanese university students.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a rapidly growing global health problem. Despite its growing incidence and potential for significant repercussions, MAFLD is still widely misunderstood and underdiagnosed. AIM: The purpose of this study was to investigate MAFLD-related knowledge, attitudes, and risk profiles among university students aged 17 to 26. METHODS: A cross-sectional study with 406 university students in Lebanon, equally distributed among males and females, was conducted using a questionnaire that includes demographics, medical information, dietary habits, physical activity, and MAFLD-related knowledge and attitudes. RESULTS: The findings demonstrated a significant lack of knowledge regarding MAFLD, with more than half of participants (54.7%) having no prior knowledge of the illness. Students exhibited unhealthy lifestyle behaviors such as smoking (68%), insufficient physical exercise (44.1%), and poor food habits (52.5%). Having a family history of heart disease, personal history of diabetes mellitus, a balanced diet and prior knowledge of the disease were associated with a higher knowledge score (p<0.05). A higher attitude score existed among those who have a personal or family history of chronic diseases and those who have a prior negative impression about the disease, prior knowledge of the disease, and those who are physically active (p<0.05). CONCLUSION: Despite knowledge gaps, university students in Lebanon have, in general, an appropriate and positive attitude towards MAFLD. We recommend the introduction of focused educational interventions to address the necessity of lifestyle changes among university students and the community as a whole. Developing comprehensive MAFLD prevention methods requires future studies in different age groups and demographics.

Multi-dimensional comparison of abdominal obesity indices and insulin resistance indicators for assessing NAFLD.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) keeps increasing annually worldwide. Non-invasive assessment tools for evaluating the risk and severity of the disease are still limited. Insulin resistance (IR) and abdominal obesity (ABO) are closely related to NAFLD. METHODS: A retrospective large-scale, population-based study was conducted based on the data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Three ABO indices, namely lipid accumulation product (LAP), visceral obesity index (VAI), waist circumference-triglyceride index (WTI), and three IR indices, including triglyceride glucose index (TyG), homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR), were analyzed and compared for their relationships with NAFLD based on weighted multivariable logistic regression, spearman correlation heatmap, smooth curve fittings. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these indices for NAFLD. Differences among the AUCs were calculated and compared by Delong test. RESULTS: In total, 3095 participants were included in our study among which 1368 adults were diagnosed with NAFLD. All six indices presented positive associations with NAFLD. There was a claw-shaped curve between HOMA-IR, VAI, LAP and NAFLD while a smooth semi-bell curve was observed in TyG, METS-IR and WTI. LAP and HOMA-IR had the best diagnostic capability for NAFLD (LAP: AUC = 0.8, Youden index = 0.48; HOMA-IR: AUC = 0.798, Youden index = 0.472) while VAI (AUC = 0.728, Youden index = 0.361) showed the lowest predictive value. The correlation heat map indicated positive correlations between all six indices and liver function, hepatic steatosis and fibrosis severity. In the NAFLD group, IR indicators presented a stronger association with alanine aminotransferase (ALT) compared with ABO indices. CONCLUSIONS: All six indices can screen NAFLD withLAP and HOMA-IR being possibly optimal predictors. IR indices may be more sensitive to identify acute hepatic injury in NAFLD patients than ABO indices.

Relationship between Neutrophil-to-Lymphocyte Ratio and Liver Fibrosis in Nonalcoholic Fatty Liver Disease Among Adults in the United States: Data from the National Health and Nutrition Examination Survey 2017-2018.

BACKGROUND/AIMS:  The relationship between neutrophil-to-lymphocyte ratio (NLR) and liver fibrosis in nonalcoholic fatty liver disease remains controversial. The aim of this study was to examine the association between NLR and liver fibrosis. MATERIALS AND METHODS:  We conducted a cross-sectional analysis using the National Health and Nutrition Examination Survey. Vibration-controlled transient elastography was used to assess liver fibrosis and its severity. Neutrophil-to-lymphocyte ratio was calculated as the ratio of neutrophil count to lymphocyte count. RESULTS:  This study included 1620 US adults with a mean age of 52.9 years, of which 53.3% were male. The obese population accounted for 62.5%, 68.5% had hypertension, 31.1% had diabetes, and 16% had significant liver fibrosis. After adjusting for all covariates, a positive correlation was observed between NLR and the severity of liver fibrosis (ß = 0.57, 95% CI = 0.22-0.92, P = .001), which remained stable across different subgroups. CONCLUSION:  This study suggests that elevated NLR levels are positively correlated with the severity of liver fibrosis in patients with nonalcoholic fatty liver disease, and these results can be well generalized to the US adult population.

Bioinformatics analysis of potential ferroptosis and non-alcoholic fatty liver disease biomarkers.

Ferroptosis plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). In this study, we aimed to use a comprehensive bioinformatics approach and experimental validation to identify and verify potential ferroptosis-related genes in NAFLD. We downloaded the microarray datasets for screening differentially expressed genes (DEGs) and identified the intersection of these datasets with ferroptosis-related DEGs from the Ferroptosis database. Subsequently, ferroptosis-related DEGs were obtained using SVM analysis; the LASSO algorithm was then used to identify six marker genes. Furthermore, the CIBERSORT algorithm was used to estimate the proportion of different types of immune cells. Subsequently, we constructed drug regulatory networks and ceRNA regulatory networks. We identified six genes as marker genes for NAFLD, demonstrating their robust diagnostic abilities. Subsequent functional enrichment analysis results revealed that these marker genes were associated with multiple diseases and play a key role in NAFLD via the regulation of immune response and amino acid metabolism, among other pathways. The expression of hepatic EGR1, IL-6, SOCS1, and NR4A1 was significantly downregulated in the NAFLD model. Our findings provide new insights and molecular clues for understanding and treating NAFLD. Further studies are needed to assess the diagnostic potential of these markers for NAFLD.

Protective role of S-adenosylmethionine on high fat/high cholesterol diet-induced hepatic and aortic lesions and oxidative stress in guinea pigs.

S-adenosylmethionine (SAM) is the main methyl group donor and has antioxidant potential. In this study, preventive and regressive potential of SAM were investigated in high fat/high cholesterol (HFHC) diet-induced non-alcoholic fatty liver disease (NAFLD) in guinea pigs. They were injected with SAM (50 mg/kg, i.p.) for 6 weeks along with HFHC diet or 4 weeks after HFHC diet. Serum transaminase activities, total cholesterol (TC), triglyceride (TG), cytochrome p450-2E1 (CYP2E1) and hydroxyproline (Hyp) levels, prooxidative and antioxidative parameters, protein expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-ß1 (TGF-ß1) together with histopathological changes were examined in the liver. SAM treatment diminished HFHC diet-induced increases in serum transaminase activities and hepatic TC, TG, CYP2E1, Hyp, α-SMA and TGF-ß1 expressions and ameliorated prooxidant-antioxidant balance. Histopathological scores for hepatic steatosis, inflammation, and fibrosis were decreased by SAM treatment. Increases in TC, diene conjugate levels, and lipid vacuoles within the tunica media of the aorta were reduced in HFHC-fed animals treated with SAM. These protective effects were also detected in the regression period of HFHC-guinea pigs due to SAM. In conclusion, SAM treatment was found to be effective in prevention and regression of HFHC-induced hepatic and aortic lesions together with decreases in oxidative stress in guinea pigs with NAFLD.

Long-term exposure to polychlorinated biphenyl 126 induces liver fibrosis and upregulates miR-155 and miR-34a in C57BL/6 mice.

Environmental pollutants, including polychlorinated biphenyls (PCBs), act as endocrine disruptors and impair various physiological processes. PCB 126 is associated with steatohepatitis, fibrosis, cirrhosis, and other hepatic injuries. These disorders can be regulated by microRNAs (miRNAs). Therefore, this study aimed to investigate the role of miRNAs in non-alcoholic fatty liver disease associated with exposure to PCB 126. Adult male C57BL/6 mice were exposed to PCB 126 (5 µmol/kg of body weight) for 10 weeks. The PCB group showed lipid accumulation in the liver in the presence of macro- and microvesicular steatosis and fibrosis with increased inflammatory and profibrotic gene expression, consistent with non-alcoholic steatohepatitis (NASH). PCB exposure also upregulated miR-155 and miR-34a, which induce the expression of proinflammatory cytokines and inflammation in the liver and reduce the expression of peroxisome proliferator-activated receptor α, which, in turn, impairs lipid oxidation and hepatic steatosis. Therefore, the present study showed that PCB 126 induced NASH via potential mechanisms involving miR-155 and miR-34a, which may contribute to the development of new diagnostic markers and therapeutic strategies.

Lipid droplets-specific fluorescent probe for wash-free imaging and in vivo diagnosis of non-alcoholic fatty liver disease.

Lipid droplets (LDs) dysfunction is closely associated with a multitude of diseases, including nonalcoholic fatty liver disease (NAFLD). Therefore, it is imperative to develop fluorescent probes that specifically target LDs for the early detection and diagnosis of NAFLD. In this study, a series of lipophilic fluorophores CZ1-CZ4 that feature a D-π-A configuration were designed and synthesized based on the carbazole and tricocyanofuran derivatives. The photophysical data revealed that all four probes exhibited large Stokes shifts (~ 120 nm) in high-polarity solvents (e.g., DMSO) and demonstrated enhanced fluorescence in solvents ranging from low-polarity (e.g., 1,4-Dioxane) to high-polarity. Notably, by utilizing probe CZ1, we could specifically visualize LDs and captured high-quality images, even eliminating the need for a time-consuming wash procedure. Moreover, CZ1 enabled monitoring of LDs dynamic changes in-real time within live cells, and importantly, it could be used to effectively distinguish normal and NAFLD tissues at both the organ and in vivo level. This exceptional property of probe CZ1 provides a practical tool for the diagnosis and intervention of NAFLD.

Are dietary factors associated with cardiometabolic risk factors in patients with non-alcoholic fatty liver disease?

Background: Non-alcoholic fatty liver disease (NAFLD) is intricately linked with dietary patterns and metabolic homeostasis. Therefore, the present study focused to investigate the relation between dietary patterns and cardiometabolic risk factors related to fatty liver in NAFLD patients. Methods: This cross-sectional study included 117 individuals whose body mass index (BMI) threshold of 25 or above diagnosed with NAFLD by magnetic resonance imaging. The hospital database was used to review the patients' medical records such as lipid parameters, and fasting blood sugar. Anthropometric measurements and body composition were measured by researchers. Likewise, data from 24-h dietary recalls of individuals were collected to analyze their energy and nutrient intakes besides calculating dietary insulin index (DII), dietary insulin load (DIL), dietary glycemic index (DGI), and dietary glycemic load (DGL). Results: Participants consuming diets with distinct levels of DII, DIL, DGI, and DGL exhibited variations in dietary energy and nutrient intake. Specifically, differences were noted in carbohydrate intake across quartiles of DII, DIL, DGI, and DGL, while fructose consumption showed variability in DGL quartiles (p ≤ 0.05). Moreover, sucrose intake demonstrated distinctions in both DII and DGL quartiles (p ≤ 0.05). No statistical difference was found in biochemical parameters and the fatty liver index among different levels of DII, DIL, DGI, and DGL (p > 0.05). After adjusting for potential confounders, participants with a higher DGI had four times greater odds of developing metabolic syndrome compared to those in the bottom quartile (OR, 4.32; 95% CI [1.42-13.11]). Conclusion: This study provides initial evidence of the intricate association between dietary factors and NAFLD, emphasizing the necessity for further research including prospective designs with larger sample sizes, to garner additional insights.

NAFLD (MASLD)/NASH (MASH): Does It Bother to Label at All? A Comprehensive Narrative Review.

Nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated steatotic liver disease (MASLD), is a liver condition that is linked to overweight, obesity, diabetes mellitus, and metabolic syndrome. Nonalcoholic steatohepatitis (NASH), or metabolic dysfunction-associated steatohepatitis (MASH), is a form of NAFLD/MASLD that progresses over time. While steatosis is a prominent histological characteristic and recognizable grossly and microscopically, liver biopsies of individuals with NASH/MASH may exhibit several other abnormalities, such as mononuclear inflammation in the portal and lobular regions, hepatocellular damage characterized by ballooning and programmed cell death (apoptosis), misfolded hepatocytic protein inclusions (Mallory-Denk bodies, MDBs), megamitochondria as hyaline inclusions, and fibrosis. Ballooning hepatocellular damage remains the defining feature of NASH/MASH. The fibrosis pattern is characterized by the initial expression of perisinusoidal fibrosis ("chicken wire") and fibrosis surrounding the central veins. Children may have an alternative form of progressive NAFLD/MASLD characterized by steatosis, inflammation, and fibrosis, mainly in Rappaport zone 1 of the liver acinus. To identify, synthesize, and analyze the scientific knowledge produced regarding the implications of using a score for evaluating NAFLD/MASLD in a comprehensive narrative review. The search for articles was conducted between 1 January 2000 and 31 December 2023, on the PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases. This search was complemented by a gray search, including internet browsers (e.g., Google) and textbooks. The following research question guided the study: "What are the basic data on using a score for evaluating NAFLD/MASLD?" All stages of the selection process were carried out by the single author. Of the 1783 articles found, 75 were included in the sample for analysis, which was implemented with an additional 25 articles from references and gray literature. The studies analyzed indicated the beneficial effects of scoring liver biopsies. Although similarity between alcoholic steatohepatitis (ASH) and NASH/MASH occurs, some patterns of hepatocellular damage seen in alcoholic disease of the liver do not happen in NASH/MASH, including cholestatic featuring steatohepatitis, alcoholic foamy degeneration, and sclerosing predominant hyaline necrosis. Generally, neutrophilic-rich cellular infiltrates, prominent hyaline inclusions and MDBs, cholestasis, and obvious pericellular sinusoidal fibrosis should favor the diagnosis of alcohol-induced hepatocellular injury over NASH/MASH. Multiple grading and staging methods are available for implementation in investigations and clinical trials, each possessing merits and drawbacks. The systems primarily used are the Brunt, the NASH CRN (NASH Clinical Research Network), and the SAF (steatosis, activity, and fibrosis) systems. Clinical investigations have utilized several approaches to link laboratory and demographic observations with histology findings with optimal platforms for clinical trials of rapidly commercialized drugs. It is promising that machine learning procedures (artificial intelligence) may be critical for developing new platforms to evaluate the benefits of current and future drug formulations.

Thermoneutrality Inhibits Thermogenic Markers and Exacerbates Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD) affects over a third of the US population and 25% globally, with current treatments proving ineffective. This study investigates whether manipulating brown adipose tissue (BAT) and beige fat activity by housing C57BL/6J mice at thermoneutral (27 °C) or standard temperatures (22 °C) impacts NAFLD development. Male mice were fed either a chow diet (CHD) or a "fast food" diet (FFD) for 10 weeks. Mice at 27 °C had reduced food intake but increased body weight and plasma leptin levels. FFD-fed mice at 27 °C had greater liver weight (2.6 vs. 1.8 g), triglyceride content (7.6 vs. 3.9 mg/g), and hepatic steatosis compared to those at 22 °C. Gene expression of fatty acid synthase, sterol regulatory element-binding protein 1, and fatty acid translocase CD36 was elevated in FFD-fed mice at 27 °C, but not in CHD-fed mice. Thermoneutral housing also reduced expression of thermogenic markers in BAT and inguinal white adipose tissue (WAT) and caused BAT whitening. In conclusion, thermoneutrality inhibits thermogenic markers and exacerbates NAFLD. Activating BAT or promoting WAT browning via cold exposure or other stimuli may offer a strategy for managing NAFLD.

Liver Fatty Acid-binding Protein Is a More Reliable Biomarker for Liver Injury in Nonalcoholic Steatohepatitis than Other Etiologies of Hepatitis.

BACKGROUND/AIMS:  Liver fatty acid-binding protein (LFABP) controls hepatocyte lipid metabolism and can be a biomarker in liver diseases. We compared the correlation of LFABP levels with liver histology in viral hepatitis and nonalcoholic fatty liver disease (NAFLD) and investigated the utility of serum LFABP as a biomarker for liver damage. MATERIALS AND METHODS:  We included 142 patients (60 chronic viral hepatitis B [CHB], 35 chronic viral hepatitis C [CHC], 47 NAFLD) and 40 healthy controls. LFABP levels were determined in all participants, and a liver biopsy was performed on patients. The nonalcoholic steatohepatitis (NASH) activity score (NAS), hepatosteatosis, liver inflammation, and fibrosis were evaluated for NAFLD patients. Ishak's histological scores were used for viral hepatitis. The correlation between LFABP levels and histologic scores was assessed in each group. RESULTS:  Serum LFABP levels in CHB, CHC, NAFLD, and control groups were 2.2, 3.5, 7.6, and 2.1 ng/mL, respectively. LFABP levels were significantly higher in the NAFLD group compared to the control, CHC, and CHB groups. LFABP was significantly higher in the NASH group than in nonalcoholic steatohepatitis, 8 ng/mL and 5.4 ng/mL, respectively (P = .001). In the NAFLD group, LFABP levels showed a moderate positive correlation with NAS score (r = 0.58, P <.001), ballooning degeneration (r = 0.67, P <.001), and lobular inflammation (r = 0.62, P <.001). A logistic regression study showed that the level of LFABP was predictive of NASH independent of age, gender, homeostasis model of IR, body mass index, aspartate aminotransferase, and alanine aminotransferase (OR = 1.869, P = .01). CONCLUSION:  LFABP specifically correlates with liver histology in NAFLD compared to viral hepatitis. Additionally, it can distinguish NASH from simple steatosis. LFABP may be a valuable biomarker for hepatocyte injury in NASH.

Honokiol Mitigates Metabolic-Associated Fatty Liver Disease by Regulating Nrf2 and RIPK3 Signaling Pathways.

BACKGROUND/AIMS:  Metabolic-associated fatty liver disease (MAFLD) is a common cause of chronic liver disease worldwide. However, there is currently no recognized effective drugs for treating it. MATERIALS AND METHODS:  In this study, we investigated the efficacy of Honokiol (HNK) in vitro for mitigating MAFLD. Then, 0.4 mM palmitic acid (PA) and LO2 cells were used to establish the MAFLD model. The protective effect of HNK on MAFLD was confirmed by Oil Red O staining and cell counting kit (CCK-8) assay in LO2 cell line. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were carried out to analyze the regulatory role of HNK on Nrf2 and RIPK3 signaling pathways. The effect of HNK and its downstream signaling pathways on oxidative stress were verified by the detection of reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD). The concentration of IL-1ß, IL-6L, and TNF-α was assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS:  The middle concentration of HNK (50 µmol/L) was selected as the best option for inhibiting lipidosis and oxidative stress in MAFLD models. Honokiol mitigates MAFLD via activation of nuclear factor E2-related factor 2 (Nrf2) signaling pathways in vitro. Honokiol suppressed MAFLD via activating the Nrf2 signaling pathway to play an antioxidant and anti-inflammatory role. Also, HNK regulates Nrf2 and RIPK3 signaling pathways to mitigate MAFLD. CONCLUSION:  Our results showed that HNK may suppress the oxidative stress and inflammation in MAFLD via activation of Nrf2 signaling pathway.

Current strategies for nonalcoholic fatty liver disease treatment (Review).

Nonalcoholic fatty liver disease (NAFLD), the most common chronic hepatic disease, has become a leading health problem worldwide. The present review summarized the methods and mechanisms to treat NAFLD, including the Mediterranean diet, physical activity and exercise, bariatric surgery and specific therapeutic agents, including statins, peroxisome proliferator­activated receptor agonists, cenicriviroc and farnesoid X receptor agonists. Biologically active substances, such as peptides, alkaloids, polyphenolic compounds, silymarin, antibiotics, fatty acids, vitamins, probiotics, synbiotics and lamiaceae have also demonstrated actions that combat NAFLD. Considering their different mechanisms of action, combining some of them may prove an efficacious treatment for NAFLD. In this light, the present review describes recent progress and future prospects in treating NAFLD.

Network analysis and experimental verification of Salvia miltiorrhiza Bunge-Reynoutria japonica Houtt. drug pair in the treatment of non-alcoholic fatty liver disease.

CONTEXT: There are currently no approved specific clinical drugs for non-alcoholic fatty liver disease (NAFLD). Salvia miltiorrhiza Bunge-Reynoutria japonica Houtt. drug pair (SRDP) has been widely used in the treatment of chronic liver diseases. However, the mechanism of SRDP treating NAFLD remains unclear. OBJECTIVE: Based on network analysis and in vitro experimental verification, we investigated the effect of SRDP on lipid deposition and explored its possible mechanism for the treatment of NAFLD. METHODS: The TCMSP platform was used to screen the active metabolites of SRDP and corresponding targets. The GeneCards and OMIM databases were used to screen the NAFLD targets. The drug-disease intersecting targets were extracted to obtain the potential targets. Then the protein-protein interaction (PPI) and drug-active metabolites-target-disease network map was constructed. The DAVID database was performed to GO and KEGG pathway enrichment analysis for the intersecting targets. The core active metabolite and signaling pathway were verified by in vitro experiments. RESULTS: Network analysis predicted 59 active metabolites and 89 targets of SRDP for the treatment of NAFLD. 112 signaling pathways were enriched for KEGG pathways, including PI3K-AKT signaling pathway,etc. It was confirmed that luteolin, the core active metabolite of SRDP, effectively reduced fat accumulation and intracellular triglyceride content in HepG2 fatty liver cell model. Luteolin could inhibit mTOR pathway by inhibiting PI3K-AKT signaling pathway phosphorylation, thereby activating autophagy to alleviate NAFLD. DISCUSSION AND CONCLUSION: The results of this study validate and predict the possible role of various active metabolites of SRDP in the treatment of NAFLD through multiple targets and signaling pathways. The core active metabolite of SRDP, luteolin can alleviate NAFLD by acting on the PI3K-AKT-mTOR signaling pathway to induce autophagy.

Immune system dysregulation in the pathogenesis of non-alcoholic steatohepatitis: unveiling the critical role of T and B lymphocytes.

Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat within the cytoplasm of hepatocytes (exceeding 5% of liver weight) in individuals without significant alcohol consumption, has rapidly evolved into a pressing global health issue, affecting approximately 25% of the world population. This condition, closely associated with obesity, type 2 diabetes, and the metabolic syndrome, encompasses a spectrum of liver disorders ranging from simple steatosis without inflammation to non-alcoholic steatohepatitis (NASH) and cirrhotic liver disease. Recent research has illuminated the complex interplay between metabolic and immune responses in the pathogenesis of NASH, underscoring the critical role played by T and B lymphocytes. These immune cells not only contribute to necroinflammatory changes in hepatic lobules but may also drive the onset and progression of liver fibrosis. This narrative review aims to provide a comprehensive exploration of the effector mechanisms employed by T cells, B cells, and their respective subpopulations in the pathogenesis of NASH. Understanding the immunological complexity of NASH holds profound implications for the development of targeted immunotherapeutic strategies to combat this increasingly prevalent and burdensome metabolic liver disease.

Ginger essential oil prevents NASH progression by blocking the NLRP3 inflammasome and remodeling the gut microbiota-LPS-TLR4 pathway in mice.

BACKGROUND: Diet and gut microbiota contribute to non-alcoholic steatohepatitis (NASH) progression. High-fat diets (HFDs) change gut microbiota compositions, induce gut dysbiosis, and intestinal barrier leakage, which facilitates portal influx of pathogen-associated molecular patterns including lipopolysaccharides (LPS) to the liver and triggers inflammation in NASH. Current therapeutic drugs for NASH have adverse side effects; however, several foods and herbs that exhibit hepatoprotection could be an alternative method to prevent NASH. METHODS: We investigated ginger essential oil (GEO) against palm oil-containing HFDs in LPS-injected murine NASH model. RESULTS: GEO reduced plasma alanine aminotransferase levels and hepatic pro-inflammatory cytokine levels; and increased antioxidant catalase, glutathione reductase, and glutathione levels to prevent NASH. GEO alleviated hepatic inflammation through mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome and LPS/Toll-like receptor four (TLR4) signaling pathways. GEO further increased beneficial bacterial abundance and reduced NASH-associated bacterial abundance. CONCLUSION: This study demonstrated that GEO prevents NASH progression which is probably associated with the alterations of gut microbiota and inhibition of the LPS/TLR4/NF-κB pathway. Hence, GEO may offer a promising application as a dietary supplement for the prevention of NASH.

Genome-wide Studies Reveal Genetic Risk Factors for Hepatic Fat Content.

Genetic susceptibility to metabolic associated fatty liver disease (MAFLD) is complex and poorly characterized. Accurate characterization of the genetic background of hepatic fat content would provide insights into disease etiology and causality of risk factors. We performed genome-wide association study (GWAS) on two noninvasive definitions of hepatic fat content: magnetic resonance imaging proton density fat fraction (MRI-PDFF) in 16,050 participants and fatty liver index (FLI) in 388,701 participants from the United Kingdom (UK) Biobank (UKBB). Heritability, genetic overlap, and similarity between hepatic fat content phenotypes were analyzed, and replicated in 10,398 participants from the University Medical Center Groningen (UMCG) Genetics Lifelines Initiative (UGLI). Meta-analysis of GWASs of MRI-PDFF in UKBB revealed five statistically significant loci, including two novel genomic loci harboring CREB3L1 (rs72910057-T, P = 5.40E-09) and GCM1 (rs1491489378-T, P = 3.16E-09), respectively, as well as three previously reported loci: PNPLA3, TM6SF2, and APOE. GWAS of FLI in UKBB identified 196 genome-wide significant loci, of which 49 were replicated in UGLI, with top signals in ZPR1 (P = 3.35E-13) and FTO (P = 2.11E-09). Statistically significant genetic correlation (rg) between MRI-PDFF (UKBB) and FLI (UGLI) GWAS results was found (rg = 0.5276, P = 1.45E-03). Novel MRI-PDFF genetic signals (CREB3L1 and GCM1) were replicated in the FLI GWAS. We identified two novel genes for MRI-PDFF and 49 replicable loci for FLI. Despite a difference in hepatic fat content assessment between MRI-PDFF and FLI, a substantial similar genetic architecture was found. FLI is identified as an easy and reliable approach to study hepatic fat content at the population level.

Pathogenic gene connections in type 2 diabetes and non-alcoholic fatty liver disease: a bioinformatics analysis and mouse model investigations experiments.

BACKGROUND: Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are prevalent metabolic disorders with overlapping pathophysiological mechanisms. A comprehensive understanding of the shared molecular pathways involved in these conditions can advance the development of effective therapeutic interventions. METHODS: We used two datasets sourced from the Gene Expression Omnibus (GEO) database to identify common differentially expressed genes (DEGs) between T2D and NAFLD. Subsequently, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to identify the enriched biological processes and signaling pathways. In addition, we performed a protein-protein interaction (PPI) network analysis to identify hub genes with pivotal roles. To validate our findings, we established a type 2 diabetic mouse model with NAFLD. RESULTS: Our analysis identified 53 DEGs shared between T2D and NAFLD. Enrichment analysis revealed their involvement in signal transduction, transcriptional regulation, and cell proliferation as well as in the ferroptosis signaling pathways. PPI network analysis identified ten hub genes, namely CD44, CASP3, FYN, KLF4, HNRNPM, HNRNPU, FUBP1, RUNX1, NOTCH3, and ANXA2. We validated the differential expression of FYN, HNRNPU, and FUBP1 in liver tissues of a type 2 diabetic mouse model with NAFLD. CONCLUSIONS: Our study offers valuable insights into the shared molecular mechanisms underlying T2D and NAFLD. The identified hub genes and pathways present promising prospects as therapeutic targets to address these prevalent metabolic disorders.