Chiglitazar attenuates high-fat diet-induced nonalcoholic fatty liver disease by modulating multiple pathways in mice.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide; however, effective intervention strategies for NAFLD are still unavailable. The present study sought to investigate the efficacy of chiglitazar, a pan-PPAR agonist, in protecting against NAFLD in mice and its underlying molecular mechanism. Male C57BL/6 J mice were fed a high-fat diet (HFD) for 8 weeks to generate NAFLD and the HFD was continued for an additional 10 weeks in the absence or presence of 5 mg/kg/d or 10 mg/kg/d chiglitazar by gavage. Chiglitazar significantly improved dyslipidemia and insulin resistance, ameliorated hepatic steatosis and reduced liver inflammation and oxidative stress in NAFLD mice. RNA-seq revealed that chiglitazar alleviated HFD-induced NAFLD in mice through multiple pathways, including fatty acid metabolism regulation, insulin signaling pathway, and AMPK signaling pathway. This study demonstrated the potential therapeutic effect of chiglitazar on NAFLD. Chiglitazar ameliorated NAFLD by modulating multiple pathways.

Polyphenols improve non-alcoholic fatty liver disease via gut microbiota: A comprehensive review.

Polyphenols, natural micronutrients derived from plants, are valued for their anti-inflammatory and antioxidant properties. The escalating global prevalence of non-alcoholic fatty liver disease (NAFLD) underscores its status as a chronic progressive liver condition. Furthermore, the dysregulation of gut microbiota (GM) is implicated in the onset and progression of NAFLD through the actions of metabolites such as bile acids (BAs), lipopolysaccharide (LPS), choline, and short-chain fatty acids (SCFAs). Additionally, GM may influence the integrity of the intestinal barrier. This review aims to evaluate the potential effects of polyphenols on GM and intestinal barrier function, and their subsequent impact on NAFLD. We searched through a wide range of databases, such as Web of Science, PubMed, EMBASE, and Scopus to gather information for our non-systematic review of English literature. GM functions and composition can be regulated by polyphenols such as chlorogenic acid, curcumin, green tea catechins, naringenin, quercetin, resveratrol, and sulforaphane. Regulating GM composition improves NAFLD by alleviating inflammation, liver fat accumulation, and liver enzymes. Furthermore, it improves serum lipid profile and gut barrier integrity. All of these components affect NAFLD through the metabolites of GM, including SCFAs, choline, LPS, and BAs. Current evidence indicates that chlorogenic acid, resveratrol, quercetin, and curcumin can modulate GM, improving intestinal barrier integrity and positively impacting NAFLD. More studies are necessary to evaluate the safety and efficacy of naringenin, sulforaphane, and catechin.

Lactucopicrin promotes fatty acid ß-oxidation and attenuates lipid accumulation through adenosine monophosphate-activated protein kinase activation in free fatty acid-induced human hepatoblastoma cancer cells.

With its annually increasing prevalence, non-alcoholic fatty liver disease (NAFLD) has become a serious threat to people's life and health. After a preliminary research, we found that Lactucopicrin has pharmacological effects, such as lowering blood lipids and protecting the liver. Further research showed its significant activation for fatty acid ß-oxidase hydroxyacyl-coenzyme A (CoA) dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), so we hypothesized that Lactucopicrin could ameliorate lipid accumulation in hepatocytes by promoting fatty acid ß-oxidation. In this study, free fatty acid (FFA)-induced human hepatoblastoma cancer cells (HepG2) were used to establish an in vitro NAFLD model to investigate the molecular basis of Lactucopicrin in regulating lipid metabolism. Staining with Oil red O and measurements of triglyceride (TG) content, fatty acid ß-oxidase (FaßO) activity, reactive oxygen species (ROS) content, mitochondrial membrane potential, and adenosine triphosphate (ATP) content were used to assess the extent to which Lactucopicrin ameliorates lipid accumulation and promotes fatty acid ß-oxidation. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot methods were used to explore the regulatory effects of Lactucopicrin on factors related to fatty acid ß-oxidation. Results showed that Lactucopicrin downregulated phosphorylated mammalian target of rapamycin (P-mTOR) by activating the adenosine monophosphate-activated protein kinase (AMPK) pathway and upregulated the messenger RNA (mRNA) and protein expression levels of coactivators (peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)), transcription factors (peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ)), and oxidative factors (carnitine palmitoyltransferase 1A (CPT1A) and HADHA). This phenomenon resulted in a significant increase in FaßO activity, ATP content, and JC-1 and a significant decrease in ROS level, TG content, and intracellular lipid droplets. With the addition of Dorsomorphin, all the effects of Lactucopicrin intervention were suppressed. In summary, Lactucopicrin promotes fatty acid ß-oxidation by activating the AMPK pathway, thereby ameliorating FFA-induced intracellular lipid accumulation in HepG2 cells.

Association between non-alcoholic fatty liver disease and metabolic abnormalities in children with different weight statuses.

OBJECTIVES: Both obesity and non-alcoholic fatty liver disease (NAFLD) increase the risk of metabolic abnormalities. However, the metabolic status of children suffering from NAFLD and exhibiting various subtypes of obesity is currently unclear. We aimed to explore the association between NAFLD and metabolic abnormalities in children with different weight statuses. METHODS: We included 6086 participants aged 6-18 years from the China Child and Adolescent NAFLD Study (CCANS), all of whom had undergone ultrasonography or magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to identify NAFLD and metabolic abnormalities, including hyperglycemia, high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), high low-density lipoprotein cholesterol, high total cholesterol, and hyperuricemia. RESULTS: Among the participants, there were 2408 children with obesity and NAFLD, 174 with NAFLD, 2396 with obesity, and 1108 without obesity and NAFLD. The odds ratios (ORs) of suffering from individual metabolic abnormalities were significantly greater in children with obesity and NAFLD than in children without obesity and NAFLD, with ORs ranging from 6.23 (95% CI: 4.56, 8.53) to 1.77 (95% CI: 1.06, 2.94). The ORs of metabolic abnormalities, except for low HDL-C, were greater in children with NAFLD alone than in children without obesity or NAFLD, with ORs ranging from 4.36 (95% CI: 2.77, 6.84) to 2.08 (95% CI: 1.14, 3.78). Notably, obesity and NAFLD had a multiplicative effect on overall metabolic abnormalities, high TG levels, and low HDL-C levels. CONCLUSIONS: Children with obesity and NAFLD could be at a significantly increased risk of metabolic abnormalities. Even for children without obesity, NAFLD appears to be associated with an increased risk of experiencing a worsened metabolic status.

Non-alcoholic fatty liver disease and heart failure: A comprehensive bioinformatics and Mendelian randomization analysis.

AIMS: Heart failure (HF) and non-alcoholic fatty liver disease (NAFLD) are significant global health issues with a complex interrelationship. This study investigates their shared biomarkers and causal relationships using bioinformatics and Mendelian randomization (MR) approaches. METHODS: We analysed NAFLD and HF datasets from the Gene Expression Omnibus (GEO). The GSE126848 dataset included 57 liver biopsy samples [14 healthy individuals, 12 obese subjects, 15 NAFL patients and 16 non-alcoholic steatohepatitis (NASH) patients]. The GSE24807 dataset comprised 12 NASH samples and 5 healthy controls. The GSE57338 dataset included 313 cardiac muscle samples [177 HF patients (95 ischaemic heart disease patients and 82 idiopathic dilated cardiomyopathy patients) and 136 healthy controls]. The GSE84796 dataset consisted of 10 end-stage HF patients and 7 healthy hearts procured from organ donors. We identified differentially expressed genes (DEGs) and constructed a protein-protein interaction (PPI) network. Functional pathways were elucidated through enrichment analyses using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneMANIA annotation. Single nucleotide polymorphism (SNP) data for HF and NAFLD were sourced from genome-wide association studies (GWAS). The HF dataset included 486 160 samples (14 262 experimental and 471 898 control), and the NAFLD dataset comprised 377 988 samples (4761 experimental and 373 227 control). MR analysis investigates the causal interrelations. RESULTS: Our analysis revealed 4032 DEGs from GSE126848 and 286 DEGs from GSE57338. The top 10 hub genes (CD163, VSIG4, CXCL10, FCER1G, FPR1, C1QB, CCR1, C1orf162, MRC1 and CD38) were significantly enriched in immune response, calcium ion concentration regulation and positive regulation of monocyte chemotaxis. CIBERSORT analysis indicated associations between these hub genes and natural killer (NK) cells and macrophages. Transcription factor (TF) target prediction for CD38, CXCL10 and CCR1 highlighted related TFs. A two-sample MR analysis confirmed a bidirectional causal relationship between NAFLD and HF. The main method [inverse variance weighted (IVW)] demonstrated a significant positive causal relationship between NAFLD and HF [P = 0.037; odds ratio (OR) = 1.024; 95% confidence interval (CI): 1.001 to 1.048]. Similarly, HF was associated with an increase in the risk of NAFLD (P < 0.001; OR = 1.117; 95% CI: 1.053 to 1.185). CONCLUSIONS: Our findings reveal novel molecular signatures common to NAFLD and HF and confirm their bidirectional causality, highlighting the potential for targeted therapeutic interventions and prompting further investigation into their intricate relationship.

Trimethylamine N-oxide induces non-alcoholic fatty liver disease by activating the PERK.

Nonalcoholic fatty liver disease (NAFLD) is a liver disease causing different progressive pathological changes. Trimethylamine N-oxide (TMAO), a product of gut microbiota metabolism, is a specific agonist of the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, one of the endoplasmic reticulum stress (ERS) pathways. TMAO has been associated with the occurrence and development of NAFLD based on the results of previous studies, but whether the simple consumption of TMAO can directly induce NAFLD and its underlying mechanism remain unclear. To investigate this question, we constructed an animal model in which adult male zebrafish were fed a controlled diet containing 1 % or 3 % TMAO for 20 weeks. Eventually, we observed that TMAO caused lipid accumulation, inflammatory infiltration, liver injury and liver fibrosis in zebrafish livers; meanwhile, the PERK signaling pathway was activated in the zebrafish livers. This finding was further confirmed in HepG2 cells and hepatic stellate cells models. In conclusion, this study found that TMAO directly induced different pathological states of NAFLD in zebrafish liver, and the activation of PERK pathway is an important mechanism, which may provide crucial strategies for the diagnosis and treatment of NAFLD.

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.

The molecular and network mechanisms of antilipidemic potential effects of Ganfule capsules in nonalcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder characterized by hepatic steatosis, inflammation and fibrosis. Ganfule (GFL), a traditional Chinese medicine, has demonstrated therapeutic potential in the treatment of NAFLD but the mechanisms involved are not fully understood.To evaluate the biochemical mechanisms of GFL in treating NAFLD by examining its effects on biological networks, key therapeutic targets, histopathological changes and clinical implications. Methods: Chemical component screening, key target prediction, biological functional enrichment analysis, lipid profile localization analysis and complex network analysis were performed on GFL using multi-database mining, network analysis and molecular docking. An NAFLD rat model was then established and treated with different doses of GFL. Histopathological evaluation and western blotting were used to verify the expression levels of key target proteins in GFL-treated NAFLD rats. Results: Network analysis analysis identified 12 core targets, 12 core active ingredients and 7 core Chinese medicinal herbs in GFL potentially involved in the treatment of NAFLD. Biological functional enrichment analysis revealed the involvement of lipid metabolism, apoptosis and intracellular signaling pathways. Molecular docking confirmed a strong affinity between GFL's core compounds and certain target proteins. Histopathological examination of an NAFLD rat model showed reduced hepatocellular steatosis after GFL treatment. Western blotting revealed significant downregulation of PPARA and PPARD protein expression and upregulation of PIK3CG and PRKACA protein expression in NAFLD rats treated with lower doses of GFL. Conclusions: Our results suggest that GFL modulates key proteins involved in lipid metabolism and apoptosis pathways. GFL improved the histopathological features of NAFLD rats by regulating lipid metabolism as well as reducing hepatocyte apoptosis and hepatocellular steatosis. These findings offer insights into the biochemical mechanism of action of GFL and support its use in the treatment for NAFLD.

Sex-specific differences in NAFLD development: effect of a high-sucrose diet on biochemical, histological, and genetic markers in C57bl/6N mice.

Sucrose intake is a potential risk factor for non-alcoholic fatty liver disease (NAFLD). Individual characteristics such as sex, play arole in the biological variation of the disease, potentially related to genetic regulation. This research evaluated sex differences in biochemical, histopathological, and gene expression responses associated with NAFLD in C57bl/6N mice on a high sucrose diet. Female and male mice were assigned to control or high sucrose diets (50% sucrose solution) for 20 weeks. After sacrifice, blood and hepatic tissue were collected for analysis. Female mice revealed moderate-to-high NAFLD, whereas male mice showed mild-to-moderate NAFLD. Sex-specific variations were observed in Cd36 gene expression, an upregulation in females compared with the male group, and Adipor1 gene expression showed significant downregulation in the female group in response to high sucrose diet compared with the control group. These findings highlight the importance of considering gender disparities in the treatment and management of NAFLD.

Outcome prediction in metabolic dysfunction-associated steatotic liver disease using stain-free digital pathological assessment.

Computational quantification reduces observer-related variability in histological assessment of metabolic dysfunction-associated steatotic liver disease (MASLD). We undertook stain-free imaging using the SteatoSITE resource to generate tools directly predictive of clinical outcomes. Unstained liver biopsy sections (n = 452) were imaged using second-harmonic generation/two-photon excitation fluorescence (TPEF) microscopy, and all-cause mortality and hepatic decompensation indices constructed. The mortality index had greater predictive power for all-cause mortality (index >.14 vs. .31 vs.

Multi-omics analysis of the biological mechanism of the pathogenesis of non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is a type of liver metabolic syndrome. Employing multi-omics analyses encompassing the microbiome, metabolome and transcriptome is crucial for comprehensively elucidating the biological processes underlying NAFLD. Methods: Hepatic tissue, blood and fecal samples were obtained from 9 NAFLD model mice and 8 normal control mice. Total fecal microbiota DNA was extracted, and 16S rRNA was amplified, to analyze alterations in the gut microbiota (GM) induced by NAFLD. Subsequently, diagnostic strains for NAFLD were screened, and their functional aspects were examined. Differential metabolites and differentially expressed genes were also screened, followed by enrichment analysis. Correlations between the differential microbiota and metabolites, as well as between the DEGs and differential metabolites were studied. A collinear network involving key genes-, microbiota-and metabolites was constructed. Results: Ileibacterium and Ruminococcaceae, both belonging to Firmicutes; Olsenella, Duncaniella and Paramuribaculum from Bacteroidota; and Bifidobacterium, Coriobacteriaceae_UCG_002 and Olsenella from Actinobacteriota were identified as characteristic strains associated with NAFLD. Additionally, differentially expressed metabolites were predominantly enriched in tryptophan, linoleic acid and methylhistidine metabolism pathways. The functions of 2,510 differentially expressed genes were found to be associated with disease occurrence. Furthermore, a network comprising 8 key strains, 14 key genes and 83 key metabolites was constructed. Conclusion: Through this study, we conducted a comprehensive analysis of NAFLD alterations, exploring the gut microbiota, genes and metabolites of the results offer insights into the speculated biological mechanisms underlying NAFLD.

Effectiveness and safety of tenofovir amibufenamide in chronic hepatitis B patients.

This letter to the editor relates to the study entitled "Tenofovir amibufenamide vs tenofovir alafenamide for treating chronic hepatitis B: A real-world study", which was recently published by Peng et al. Hepatitis B virus infection represents a significant health burden worldwide and can lead to cirrhosis and even liver cancer. The antiviral drugs currently used to treat patients with chronic hepatitis B infection still have many side effects, so it is crucial to identify safe and effective drugs to inhibit viral replication.

Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common liver disorder worldwide, with an estimated global prevalence of more than 31%. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide a comprehensive analysis of the extrahepatic manifestations of MASH, focusing on chronic diseases related to the cardiovascular, muscular, and renal systems. A systematic review of published studies and literature was conducted to summarize the findings related to the systemic impacts of MASLD and MASH. The review focused on the association of MASLD and MASH with metabolic comorbidities, cardiovascular mortality, sarcopenia, and chronic kidney disease. Mechanistic insights into the concept of lipotoxic inflammatory "spill over" from the MASH-affected liver were also explored. MASLD and MASH are highly associated (50%-80%) with other metabolic comorbidities such as impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, and hypertension. Furthermore, more than 90% of obese patients with type 2 diabetes have MASH. Data suggest that in middle-aged individuals (especially those aged 45-54), MASLD is an independent risk factor for cardiovascular mortality, sarcopenia, and chronic kidney disease. The concept of lipotoxic inflammatory "spill over" from the MASH-affected liver plays a crucial role in mediating the systemic pathological effects observed. Understanding the multifaceted impact of MASH on the heart, muscle, and kidney is crucial for early detection and risk stratification. This knowledge is also timely for implementing comprehensive disease management strategies addressing multi-organ involvement in MASH pathogenesis.

Excess cardiovascular mortality in men with non-alcoholic fatty liver disease: A cause for concern!

Non-alcoholic fatty liver disease (NAFLD) has emerged as the commonest cause of chronic liver disease worldwide in recent years. With time, our understanding of NAFLD has evolved from an isolated liver condition to a systemic disease with significant manifestations beyond the liver. Amongst them, cardiovascular diseases (CVDs) are the most important and clinically relevant. Recent research supports a strong independent link between NALFD and CVD beyond the shared risk factors and pathophysiology. Female sex hormones are well known to not only protect against CVD in pre-menopausal females, but also contribute to improved adipose tissue function and preventing its systemic deposition. Recent research highlights the increased risk of major adverse cardiovascular-cerebral events (MACCE) amongst male with NAFLD compared to females. Further, racial variation was observed in MACCE outcomes in NAFLD, with excess mortality in the Native Americans and Asian Pacific Islanders compared to the other races.

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.

Ultrasound-estimated hepatorenal index: diagnostic performance and interobserver agreement for pediatric liver fat quantification.

BACKGROUND: Semiquantitative and quantitative sonographic techniques have the potential for screening and surveillance of children at risk of nonalcoholic fatty liver disease. OBJECTIVE: To determine diagnostic performance and interobserver agreement of hepatorenal index (HRI) for pediatric ultrasound-based liver fat quantification. MATERIALS AND METHODS: In an institutional review board (IRB)-approved retrospective study (April 2014 to April 2023), children (< 18 years) with clinically performed magnetic resonance imaging (MRI) scans for liver fat quantification were assessed. Inclusion criteria required availability of abdominal ultrasound within 3 months of quantitative MRI. Three blinded readers subjectively assessed for sonographic hepatic steatosis and calculated HRI. MRI proton density fat fraction (PDFF) was the reference standard. Interobserver agreement, correlation with PDFF, and optimal HRI (using ROC analysis) values were analyzed. The significance level was set at p < 0.05. RESULTS: A total of 41 patients (25 male) with median (interquartile range (IQR)) age of 13 (10-15) years were included. Median (IQR) MRI PDFF was 11.30% (2.70-17.95%). Hepatic steatosis distribution by MRI PDFF included grade 0 (34%), grade 1 (15%), grade 2 (22%), and grade 3 (29%) patients. Intraclass correlation coefficient for HRI among the three readers was 0.61 (95% CI 0.43-0.75) (p < 0.001). Moderate correlation was observed between manually estimated HRI and PDFF for each reader (r = 0.62, 0.67, and 0.67; p < 0.001). Optimal HRI cutoff was found to be 1.99 to diagnose hepatic steatosis (sensitivity 89%, specificity 93%). Median (IQR) HRI for each MRI grade of hepatic steatosis (0-4) was as follows: 1.2 (1.1-1.5), 2.6 (1.1-3.3), 3.6 (2.6-5.4), 5.6 (2.6-10.9), respectively (p < 0.001). CONCLUSION: Ultrasound-estimated HRI has moderate interobserver agreement and moderate correlation with MRI-derived PDFF. HRI of 1.99 maximizes accuracy for identifying pediatric liver fat.

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.

Advances in clinical research on glucagon.

We are now celebrating the 100th anniversary of the discovery of an important pancreatic hormone, glucagon. Glucagon is historically described as a diabetogenic hormone elevating glucose levels via increases in insulin resistance and hepatic gluconeogenesis. The more recently identified actions of glucagon include not only its pathophysiologic effects on glucose metabolism but also its significant roles in amino-acid metabolism in the liver. The possibility that abnormalities in α-cells' secretion of glucagon in metabolic disorders are a compensatory adaptation for the maintenance of metabolic homeostasis is another current issue. However, the clinical research concerning glucagon has been considerably behind the advances in basic research due to the lack of suitable methodology for obtaining precise measurements of plasma glucagon levels in humans. The precise physiology of glucagon secretory dynamics in individuals with metabolic dysfunction (including diabetes) has been clarified since the development in 2014 of a quantitative measurement technique for glucagon. In this review, we summarize the advances in the clinical research concerning glucagon, including those of our studies and the relevant literature.

Alcoholic Liver Disease/Non-Alcoholic Fatty Liver Disease Index for Classification of Patients with Steatotic Liver Disease.

Background: Steatotic liver disease (SLD) encompasses metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (AALD) at extremes as well as an overlap group termed MASLD with increased alcohol intake (Met-ALD). The Alcoholic Liver Disease/Non-Alcoholic Fatty Liver Disease Index (ANI) was proposed to differentiate ALD from non-alcoholic fatty liver disease (NAFLD). We analysed the performance of the ANI in differentiating within the SLD spectrum. Methods: In a cross-sectional study at a tertiary care center, 202 adults (>18 years) who were prospectively diagnosed with SLD defined by magnetic resonance imaging-proton density fat fraction >6.4% were enrolled. Alcohol consumption (AC) was recorded according to thresholds for significant AC: 140-350 g/week (or 20-50 g/day) for females and 210-420 g/week (or 30-60 g/day) for males. The ANI was calculated, and area under the receiver operating characteristic curve (AUROC) was generated. Results: Of 202 patients (47 years [interquartile range, IQR, 38 to 55], 23.75% females, 77% obese, 42.1% diabetic, 38.1% hypertensive, 28.7% statin use), 40.5% were ever-alcohol consumers; 120 (59%), 50 (24.7%), and 32 (15.8%) were MASLD (ANI, -3.7 [IQR, -7 to -1.6]; Met-ALD, - 1.45 [IQR, -2.4 to 0.28]; and AALD, 0.71 [IQR, -1.3 to 4.8], respectively; P<0.05 for all). The AUROC of the ANI for MASLD and AALD was 0.79 (0.72 to 0.84; cut-off <-3.5) and 0.80 (0.74 to 0.86; cut-off >-1.49), respectively. The ANI outperformed aspartate transaminase/alanine transaminase (AST/ALT) ratio (AUROC=0.75 [0.69 to 0.81]) and gamma glutamyl transpeptidase (GGT) (AUROC=0.74 [0.67 to 0.80]). Addition of GGT did not improve model performance (AUCdiff=0.004; P=0.33). Conclusion: AC is common in MASLD. The ANI distinguishes MASLD and AALD, with individual cut-offs within the intermediate zone indicating Met-ALD. ANI also outperforms AST/ALT ratio or GGT.

In vitro osteoclast differentiation enhanced by hepatocyte supernatants from high-fat diet mice.

Non-alcoholic fatty liver disease (NAFLD) is associated with abnormal bone metabolism, potentially mediated by elevated levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-ɑ) and interleukin 6 (IL-6). This study aims to investigate the direct regulatory effects of liver tissues on osteoblast and osteoclast functions in vitro, focusing on the liver-bone axis in NAFLD. Twelve-week-old C57BL/6 mice were fed either a control diet or a high-fat diet (HFD) for 12 weeks. Bone structural parameters were assessed using microCT. Primary hepatocyte cultures were established from control and HFD-fed C57BL/6 mice, as well as IL-6-/- and TNF-α-/- mice. The supernatants from these hepatocyte cultures were used to induce differentiation in bone marrow cell-derived osteoblasts and osteoclasts in vitro. Results showed that mice on a HFD exhibited increased lipid infiltration in liver and bone marrow tissues, alongside reduced bone mass. Moreover, the supernatants from hepatocyte cultures from mice on a HFD displayed elevated TNF-α and IL-6 levels. These supernatants, particularly those derived from HFD-fed and IL-6-/- mice, significantly enhanced osteoclast differentiation in vitro. In contrast, supernatants from TNF-α-/- mice did not significantly affect osteoblast or osteoclast differentiation in vitro. In conclusions, this current study suggested that fatty liver tissues may negatively impact bone metabolism. Additionally, knockout of TNF-α and IL-6 genes revealed distinct influence on osteoblast and osteoclast functions, highlighting the complex interplay between live pathology and bone health.