Fatty Liver Research Articles

Jiawei Qi Gong Wan improves liver fibrosis and inflammation in PCOS mice via the Akt2-FoxO1 and YAP/TAZ signaling pathways

BackgroundMetabolic disorders in polycystic ovary syndrome (PCOS) patients have attracted increasing attention, and nonalcoholic fatty liver disease (NAFLD) in particular has been the focus of much research due to its high incidence and potential harm in patients with PCOS. However, little is known about whether PCOS is associated with more severe NAFLD histopathology. Although Jiawei Qi Gong Wan (JQGW) is widely used clinically, its specific effects and mechanisms on the liver remain unclear. PurposeThe aim of this study was to explore the mechanism of JQGW in improving metabolic abnormalities in the liver in PCOS mice in order to support the development of therapies to prevent PCOS complications. MethodsA mouse model of PCOS was established by subcutaneously implanting letrozole tubes. The effect of JQGW on liver metabolism in mice was observed by measuring biochemical indicators in serum. Liver morphological changes were observed using hematoxylin and eosin staining along with Sirius red staining, while Western blotting and qRT-PCR were used to quantify the expression of genes and proteins related to liver fibrosis and inflammation processes. Network pharmacology was used to analyze the key factors that JQGW may target in improving liver fibrosis in PCOS mice, and the results were verified by Western blotting of liver tissue from PCOS mice. ResultsPCOS mice had obvious liver metabolic dysfunction, inflammation, and fibrosis, all of which could be reversed by JQGW. Network pharmacology functional enrichment revealed that the overlapping targeted genes were enriched mainly in insulin resistance-related pathways and androgen-related pathways. We verified related proteins and found that JQGW improved liver fibrosis and inflammation in PCOS mice mainly by regulating the Akt2-FoxO1 and YAP/TAZ signaling pathways. ConclusionJQGW can improve liver metabolic function in a letrozole-induced PCOS mouse model by inhibiting liver fibrosis and inflammation, and it acts mechanistically by regulating the Akt2-FoxO1 and YAP/TAZ signaling pathways. Our findings thus provide a valuable reference for the advancement of therapeutic strategies aimed at addressing PCOS patients with abnormal liver metabolism.

Peanut Shell Extract Improves Markers of Glucose Homeostasis in Diabetic Mice by Modulating Gut Dysbiosis and Suppressing Inflammatory Immune Response

Background/Objective: There is strong evidence that the tripartite interaction between glucose homeostasis, gut microbiota, and the host immune system plays a critical role in the pathophysiology of type 2 diabetes mellitus (T2DM). We reported previously that peanut shell extract (PSE) improves mitochondrial function in db/db mice by suppressing oxidative stress and inflammation in the liver, brain, and white adipose tissue. This study evaluated the impacts of PSE supplementation on glucose homeostasis, liver histology, intestinal microbiome composition, and the innate immune response in diabetic mice. Methods: Fourteen db/db mice were randomly assigned to a diabetic group (DM, AIN-93G diet) and a PSE group (1% wt/wt PSE in the AIN-93G diet) for 5 weeks. Six C57BL/6J mice received the AIN-93G diet for 5 weeks (control group). Parameters of glucose homeostasis included serum insulin, HOMA-IR, HOMA-B, and the analysis of pancreatic tissues for insulin and glucagon. We assessed the innate immune response in the colon and liver using a microarray. Gut microbiome composition of cecal contents was analyzed using 16S rRNA gene amplicon sequencing. Results: PSE supplementation improved glucose homeostasis (decreased serum insulin concentration, HOMA-IR, and HOMA-B) and reduced hepatic lipidosis in diabetic mice. PSE supplementation reversed DM-induced shifts in the relative abundance of amplicon sequence variants of Enterorhabdus, Staphylococcus, Anaerotruncus, and Akkermansia. Relative to the DM mice, the PSE group had suppressed gene expression levels of Cd8α, Csf2, and Irf23 and increased expression levels of Tyk2, Myd88, and Gusb in the liver. Conclusions: This study demonstrates that PSE supplementation improves T2DM-associated disorders of diabetic mice, in part due to the suppression of innate immune inflammation.

Impact of Dietary Niacin on Metabolic Dysfunction-Associated Steatotic Liver Disease in Mediterranean Subjects: A Population-Based Study

Background: The impact of dietary niacin on metabolic dysfunction-associated steatotic liver disease (MASLD) is elusive. This sub-study aimed to investigate the relationship between dietary niacin intake and the presence of MASLD in participants from two Catalonian cohorts. Methods: A total of 222 subjects with MASLD were age- and sex-matched to 222 non-MASLD subjects. Dietary nutrients were analyzed using a validated food frequency questionnaire (FFQ). Dietary niacin and other nutrients were adjusted for total energy intake. MASLD was defined by a Fatty Liver Index (FLI) of >60 and by having at least one component of metabolic syndrome. The association between niacin intake (distributed into tertiles) and the presence of MASLD was assessed using multivariate logistic regression. Potential non-linear relationships were also analyzed through restricted cubic spline regression (RCS). Results: Our data revealed that subjects with MASLD had worse metabolic profiles. The dietary intake of niacin did not differ between subjects with and without MASLD. Even after adjusting for different confounding variables, i.e., sociodemographic variables, smoking status, physical activity, and cardiometabolic comorbidities, no significant associations were observed between higher intakes of niacin (tertiles 2 and 3) and the presence of MASLD: odds ratio (95% confidence) second tertile: 0.99 (0.89–1.09); third tertile: 0.98 (0.89–1.10). However, RCS analysis uncovered a significant non-linear dose-response association between dietary niacin intake and odds of MASLD. Specifically, such analysis revealed that MASLD risk was decreased in subjects with niacin intake values of <35 mg/day. Conclusions: Our data showed that dietary niacin intake was associated with lower odds of MASLD in a Mediterranean population; however, our logistic regression analysis failed to reveal significant associations between the intake of niacin and the risk of MASLD. Further research is warranted to establish a causal relationship between dietary niacin interventions and MASLD.

Impaired chaperone-mediated autophagy leads to abnormal SORT1 (sortilin 1) turnover and CES1-dependent triglyceride hydrolysis

ABSTRACT SORT1 (sortilin 1), a member of the the Vps10 (vacuolar protein sorting 10) family, is involved in hepatic lipid metabolism by regulating very low-density lipoprotein (VLDL) secretion and facilitating the lysosomal degradation of CES1 (carboxylesterase 1), crucial for triglyceride (TG) breakdown in the liver. This study explores whether SORT1 is targeted for degradation by chaperone-mediated autophagy (CMA), a selective protein degradation pathway that directs proteins containing KFERQ-like motifs to lysosomes via LAMP2A (lysosomal-associated membrane protein 2A). Silencing LAMP2A or HSPA8/Hsc70 with siRNA increased cytosolic SORT1 protein levels. Leupeptin treatment induced lysosomal accumulation of SORT1, unaffected by siLAMP2A co-treatment, indicating CMA-dependent degradation. Human SORT1 contains five KFERQ-like motifs (658VVTKQ662, 730VREVK734, 733VKDLK737, 734KDLKK738, and 735DLKKK739), crucial for HSPA8 recognition; mutating any single amino acid within these motifs decreased HSPA8 binding. Furthermore, compromised CMA activity resulted in elevated SORT1-mediated degradation of CES1, contributing to increased lipid accumulation in hepatocytes. Consistent with in vitro findings, LAMP2A knockdown in mice exacerbated high-fructose diet-induced fatty liver, marked by increased SORT1 and decreased CES1 levels. Conversely, LAMP2A overexpression promoted SORT1 degradation and CES1D accumulation, counteracting fasting-induced CES1D suppression through CMA activation. Our findings reveal that SORT1 is a substrate of CMA, highlighting its crucial role in directing CES1 to lysosomes. Consequently, disrupting CMA-mediated SORT1 degradation significantly affects CES1-dependent TG hydrolysis, thereby affecting hepatic lipid homeostasis.

Coronary Artery Disease and Major Adverse Cardiovascular Events in People With Hepatic Steatosis at Low Atherosclerotic Cardiovascular Disease Risk.

Hepatic steatosis (HS) and 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 7.5% are associated with increased risk for cardiovascular events. To assess underlying coronary artery disease (CAD) and major adverse cardiovascular event (MACE) among those with and without HS at different ASCVD risk. We evaluated stable chest pain patients receiving coronary computed tomography (CT) in the PROMISE trial. HS and CAD endpoints were defined on coronary CT. MACE was defined as unstable angina, non-fatal myocardial infarction, and all-cause death. Multivariable Cox regression, adjusting for CAD characteristics, assessed the association of HS with MACE for ASCVD < 7.5%. One thousand two hundred and four of 3702 (32.5%) patients were at ASCVD < 7.5% and 20.3% (244/1204) of them had HS. Individuals with HS were younger (54.3 ± 5.2 vs. 55.8 ± 5.2; p < 0.001), more often males (40.2% [98/244] vs. 27.1% [260/960]; p < 0.001), had more risk factors/person (2.06 ± 0.89 vs. 1.93 ± 0.91; p = 0.047). CAD characteristics were similar between HS vs. non-HS patients at ASCVD < 7.5% and ASCVD ≥ 7.5% (all p > 0.05). Patients with HS had greater MACE rate compared to non-HS patients (ASCVD < 7.5%: 3.75%[9/244] vs. 1.5% [14/960]; p = 0.027 and ASCVD ≥ 7.5%: 4.7% [33/696] vs. 3.1% [56/1802]; p = 0.043). In patients without HS, MACE rate was higher in the ASCVD ≥ 7.5% vs. < 7.5% (3.1% [56/1802] vs. 1.5% [14/960]; p = 0.011). In patients with HS, MACE rates were not significantly different between ASCVD ≥ 7.5% vs. < 7.5% (4.7% [33/696] vs. 3.7% [9/244]; p = 0.484). In ASCVD < 7.5%, HS predicted MACE (aHR:2.34, 95%CI:1.01-5.43; p = 0.048), independent of CAD characteristics. Individuals with HS at ASCVD < 7.5% risk had similar CAD characteristics as patients without HS at < 7.5% ASCVD risk, yet experienced comparable MACE rates as those at ASCVD ≥ 7.5%.

Anti-b diminishes hyperlipidaemia and hepatic steatosis in hamsters and mice by suppressing the mTOR/PPARγ and mTOR/SREBP1 signalling pathways.

As a chronic metabolic syndrome, hyperlipidaemia is manifested as aberrantly elevated cholesterol and triglyceride (TG) levels, primarily attributed to disorders in lipid metabolism. Despite the promising outlook for hyperlipidaemia treatment, the need persists for the development of lipid-lowering agents with heightened efficiency and minimal toxicity. This investigation aims to elucidate the lipid-lowering effects and potential pharmacodynamic mechanisms of Anti-b, a novel low MW compound. We employed high-fat diet (HFD) in hamsters and mice or oleic acid (OA) in cultures of HepG2 cells and LO2 cells to induce hyperlipidaemia models. We administered Anti-b to assess its therapeutic effects on dyslipidaemia and hepatic steatosis. We used western blotting, RNA sequencing, GO and KEGG analysis, oil red O staining, along with molecular docking and molecular dynamics simulation to elucidate the mechanisms underlying the effects of Anti-b. Anti-b exhibited a substantial reduction in HFD-induced elevation of blood lipids, liver weight to body weight ratio, liver diameter and hepatic fat accumulation. Moreover, Anti-b demonstrated therapeutic effects in alleviating total cholesterol (TC), TG levels, and lipid accumulation derived from OA in HepG2 cells and LO2 cells. Mechanistically, Anti-b selectively bound to the mTOR kinase protein and increased mTOR thermal stability, resulting in downregulation of phosphorylation level. Notably, Anti-b exerted anti-hyperlipidaemia effects by modulating PPARγ and SREBP1 signalling pathways and reducing the expression level of mSREBP1 and PPARγ proteins. In conclusion, our study has provided initial data of a novel low MW compound, Anti-b, designed and synthesised to target mTOR protein directly. Our results indicate that Anti-b may represent a novel class of drugs for the treatment of hyperlipidemia and hepatic steatosis.

Gut microbiota and mycobiota change with feeding duration in mice on a high-fat and high-fructose diet

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is becoming the most common chronic liver disease. The gut microbiome is regarded to play a crucial role in MAFLD, but the specific changes of gut microbiome, especially fungi, in different stages of MAFLD are not well understood. This study aimed to observe the longitudinal changes of colon bacteria and fungi of mice at different feeding duration of a high-fat and high-fructose diet (HFHFD), and explore the association between the changes and the progression of MAFLD.MethodsTwenty-eight male C57BL6J mice were randomly assigned to the normal diet (ND) group and HFHFD group. At the 8th and 16th weeks, mice were sacrificed to compare the diversity, composition, and co-abundance network of bacteria and fungi in colon contents among groups.ResultsHFHFD-8W mice exhibited increases in Candida and Dorea, and decreases in Oscillospira and Prevotella in comparison to ND-8W mice, HFHFD-16W mice had increases in Bacteroides, Candida, Desulfovibrio, Dorea, Lactobacillus, and Rhodotorula, and decreases in Akkermansia, Aspergillus, Sterigmatomyces, and Vishniacozyma in comparison to ND-16W mice. And compared to HFHFD-8W mice, HFHFD-16W mice had increases in Desulfovibrio, Lactobacillus, Penicillium, and Rhodotorula, and decreases in Talaromyces and Wallemia. Spearman and GEE correlation analysis revealed that Bacteroides, Candida, Desulfovibrio, and Lactobacillus positively correlated with NAFLD activity score (NAS).ConclusionGut microbiota and mycobiota undergo diverse changes at different stages of MAFLD.Clinical trial numberNot applicable.

Aspartate aminotransferase-to-platelet ratio index outperforms Fibrosis-4 in 2843 Korean patients with metabolic dysfunction-associated steatotic liver disease.

The definition of metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed. We aim to investigate the diagnostic efficacy of noninvasive fibrosis markers in predicting liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), and MASLD. This retrospective study involved 2843 patients diagnosed with steatotic liver disease at six tertiary hospitals in South Korea. Liver fibrosis was assessed using vibration-controlled transient elastography, and various noninvasive markers, including the aspartate aminotransferase-to-platelet ratio index (APRI), Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and serum Mac-2-binding protein glycosylation isomer were analyzed. Among 1106 patients, 79.9% met criteria for NAFLD, MAFLD, and MASLD. The APRI had area under the receiver operating characteristic curve (AUC) values of 0.819, 0.821, and 0.818 for liver fibrosis≥F2, and 0.819, 0.824, and 0.884 for liver fibrosis≥F3, and 0.890, 0.884, and 0.889 for fibrosis≥F4 in NAFLD, MAFLD, and MASLD, respectively. The FIB-4 index showed AUC values of 0.776, 0.793, and 0.778 for fibrosis≥F2, 0.788, 0.814, and 0.79 for fibrosis≥F3, and 0.846, 0.859, and 0.856 for fibrosis≥F4. The APRI consistently had the highest AUC values, except in individuals older than 64years for fibrosis≥F4. The APRI was the most effective noninvasive fibrosis marker across NAFLD, MAFLD, and MASLD, particularly in age-stratified analyses. Further research is needed to establish standardized cut-off values and enhance the clinical utility of these markers in managing liver fibrosis.

Seasonal Dynamics of Caligus clemensi Infestation in European Seabass and Flathead Grey Mullet Integrating Morphological, Molecular, Immunological, and Environmental Perspectives

This case study investigates the seasonal prevalence, morphological characteristics, molecular identity, host immune response, and environmental factors influencing Caligus clemensi infestations in farmed European seabass and flathead grey mullet at a single marine fish farm. A total of 600 fish (400 seabass, 200 mullet) were examined over one year, revealing seasonal fluctuations in parasite prevalence and intensity. C. clemensi infestation peaked in winter for seabass (75% prevalence) and spring for grey mullet (80% prevalence), with notable declines in summer and autumn for both species. Morphological analysis confirmed C. clemensi as the causative agent, exhibiting sexual dimorphism and characteristic features including a quadrilateral cephalothorax and disk-shaped lunules. Molecular characterization of the 18S rRNA gene corroborated the morphological identification, with phylogenetic analysis revealing a well-supported monophyletic clade for C. clemensi within the family Caligidae. Quantitative real-time PCR demonstrated significantly elevated interleukin-1β (IL-1β) expression in infected fish, indicating a robust inflammatory response. Grey mullet and seabass exhibited high IL-1β upregulation. Histopathological examination revealed severe gill tissue damage, vascular changes, and hepatic steatosis in infected fish. Water quality analysis identified several parameters exceeding permissible limits, including total suspended solids (4800-5100 mg/L), total dissolved solids (32000 mg/L), sulfates (2300 mg/L), and chlorides (18000 mg/L). These elevated levels, likely associated with nearby oil production and refining activities, created conditions conducive to parasite proliferation. The high total suspended solids might provide substrates for C. clemensi settlement and attachment, while increased dissolved ions could stress fish and reduce their parasite resistance. This multidisciplinary case study revealed complex host-parasite interactions between C. clemensi and farmed marine fish, highlighting the need for improved water quality and targeted parasite control to enhance aquaculture sustainability in the Suez Canal region.

Slow Metabolism-Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone-Induced Obesity-Specific Liver Injury.

Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug-induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated. Given the significance of BBR and its analogs in anti-gout/hyperuricemia drug discovery, elucidating the mechanism by which BBR exacerbates obesity-specific DILI warrants further investigation. In this study, through a combined multi-omics, pharmacological, and pharmacokinetic approaches, it is found that BBR-induced obesity-specific DILI is primarily through the potentiation of peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways. Further in vivo and in vitro pharmacokinetic analyses reveal that obese db/db mice exhibited a diminished capacity to metabolize BBR in their livers. This reduction leads to prolonged retention of BBR, subsequently resulting in chronic and sustained hepatic PPARγ agonism. This study demonstrates that a slow metabolism-driven amplification of hepatic PPARγ agonism mediates BBR-induced obesity-specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre-existing NAFLD in both clinical practice and drug discovery processes.

Forns index and fatty liver index, but not FIB-4, are associated with indices of glycaemia, pre-diabetes and type 2 diabetes: analysis of The Maastricht Study

ObjectiveGlucose metabolism status (GMS) is linked to non-alcoholic fatty liver disease (NAFLD). Higher levels of advanced glycation end products (AGEs) are observed in people with type 2 diabetes mellitus (T2DM)...

Non-alcoholic fatty liver disease and the gut microbiota in adolescents: is there a relationship?

BackgroundDespite the increasing prevalence of nonalcoholic fatty liver disease (NAFLD), the pathophysiology is still not fully understood. Recent evidence suggests that the gut microbiota may play a role in the pathophysiology of NAFLD and may also offer new therapeutic options.MethodsThis prospective cross-sectional study included 100 consecutive newly diagnosed obese patients (BMI ≥ 95th percentile), aged 14–18 years with NAFLD (confirmed by ultrasound), persistently elevated levels of alanine aminotransferase (ALT) greater than 60 U/L for 1–6 months, and 100 healthy controls. We evaluated changes in the gut microbiota in NAFLD adolescents compared with healthy controls.ResultsAccording to the multiple logistic regressions, the variables associated with NAFLD were the presence of Clostridium difficile, the presence of Salmonella spp., a greater abundance of Bifidobacterium and Prevotella, and a lower abundance of Lactobacillus.ConclusionChanges in the gut microbiota occur in adolescents with NAFLD compared with healthy individuals, which may be useful for identifying youths who are amenable to gut microbiota-based interventions.Clinical trial numberNot applicable.

Gallic acid ameliorates diabetic steatohepatitis in db/db mice fed with a high-fat diet

The term nonalcoholic fatty liver disease has been changed to metabolic dysfunction–associated steatotic liver disease (MASLD). MASLD and metabolic dysfunction–associated steatohepatitis (MASH) are complications arising from increased lipid accumulation in the liver. Previous studies have indicated that gallic acid (GA) induces immune modulation. In this study, we examined the effectiveness of GA in reducing serum lipid levels and lipid deposition in the liver and ameliorating steatohepatitis in a diabetic mouse model fed with a high-fat diet (HFD). Animal studies were conducted using db/m mice as the normal control group and db/db mice fed with a normal diet, db/db mice fed with an HFD, and db/db mice fed with an HFD supplemented with GA as the study groups. The serum parameters were higher in the db/db group than in the normal control group. The serum lipid profiles and liver fatty scores were significantly higher in the HFD group than in the db/m and db/db groups. However, the levels of liver antioxidants were significantly lower in the HFD group than in the db/m and db/db group. When diabetic mice were fed with both an HFD and GA, an improvement was observed in the serum lipid profiles and liver fatty deposition, with the amelioration of steatohepatitis and enhancement of liver antioxidant activity. GA inhibits MASH by upregulating the expression of miR-30a-3p and downregulating the expression of NF-κB. GA also increases the levels of antioxidant enzymes and ameliorates MASH in HFD-fed diabetic mice.

Exploring the relationship between air pollution, non-alcoholic fatty liver disease, and liver function indicators: a two-sample Mendelian randomization analysis study

Exploring the relationship between air pollution, non-alcoholic fatty liver disease, and liver function indicators: a two-sample Mendelian randomization analysis study

Liposomal delivery of Annona muricata leaves extract for the treatment of hepatocellular carcinoma

Background Liver in the body plays vital role including digestion, detoxification, metabolism and even production of hormones. Hepatocellular carcinoma is recognized as one of leading cause of death worldwide. Infection with hepatitis B and C virus, nonalcoholic fatty liver disease and excessive consumption of alcohol are among the most common risk factors associated with the development of hepatocellular carcinoma. Objective The present research study involves formulation of liposomal delivery of methanolic extract of Annona muricata as an alternative for the treatment of hepatocellular carcinoma. Methods The methanolic extract of Annona muricata was subjected for both nonvolatile and volatile content analysis by performing phytochemical screening and GCMS. The methanolic extract was entrapped within the liposomes for its effective delivery. The prepared liposomes were characterized in-vitro, and the optimized formulation was further evaluated against hepatocellular carcinoma induced in the animal model. Results The methanolic extract showed the presence of alkaloid, carbohydrate, flavonoid, tannin, proteins and acetogenins, whereas the GMCS analysis depicts presence of 12 different compounds. The optimized in-vitro analysis of prepared liposomes showed a particle size of 107.2 ± 1.7 nm, zeta potential of −30.6 mV and entrapment efficiency of 62.15%. TEM micrograph of the optimized liposome formulation has showed spherical geometry with homogenous distribution and negligible agglomeration. In-vivo anticancer study reveals the potent efficacy of the formulation for the treatment of hepatocellular carcinoma. Conclusion The research findings have established the efficacy of the methanolic extract of Annona muricata in the treatment of hepatocellular carcinoma.

Microbiome and Chronic Disease

The origin of “microbiota” can be dated back to early 1900s. It was found that a vast number of microorganisms, including bacteria, yeasts, and viruses, coexist in various sites of the human body (gut, skin, lung, oral cavity). The gut microbiome, in particular, has been closely linked to metabolic conditions such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). Dysbiosis, or an imbalance in the gut microbiota, can impair the gut's ability to regulate metabolism, insulin sensitivity, and inflammation. Key mechanisms by which the microbiome affects metabolic diseases include: Short-chain fatty acids (SCFAs), inflammation and energy harvest. The gut microbiome is crucial for regulating metabolism, energy balance, and immune function. Disruptions in the gut microbiome have been associated with conditions such as obesity, type 2 Diabetes and non-alcoholic fatty liver disease (NAFLD).Maintaining a healthy microbiome through a balanced diet, regular exercise, and careful use of antibiotics can help reduce the risk of conditions like obesity, type 2 diabetes, cardiovascular disease, autoimmune disorders, and even some cancers. As research in this area continues to evolve, the microbiome may become a key target for the prevention and treatment of chronic diseases.

Prevalence trends of type 2 diabetes treatment, dyslipidemia and hepatic steatosis in Northeast Germany.

The investigation of prevalence trends of metabolic cardiovascular risk factors is important for appropriate planning of future health programs aiming to prevent cardiovascular morbidity and mortality. In a previous study, we demonstrated an increase in the prevalence of type 2 diabetes (T2D) between 2000 and 2010 in Northeast Germany. The purpose of this study is to investigate prevalence trends of T2D treatment, dyslipidemia and hepatic steatosis in Northeast Germany. The baseline examinations of the first Study of Health in Pomerania (SHIP) project were carried out from 1997 to 2001 (SHIP-START-0, 4308 subjects). A second, independent random sample of the same region was enrolled between 2008 and 2012 (SHIP-TREND-0, 4420 subjects). All data were standardized with post-stratification weighting derived from the adult population of the German federal state of Mecklenburg-West Pomerania. The prevalence of metformin intake increased from 2.1% to 4.1% and insulin use from 2.0% to 2.8%. While the prevalence of statin intake increased from 6.8% to 12.2%, the prevalence of dyslipidemia decreased slightly from 49.0% in SHIP-START-0 to 45.5% in SHIP-TREND-0. The prevalence of hepatic steatosis increased from 29.7% to 37.3%. This increase was most prominently observed in women and younger age groups. T2D, dyslipidemia and hepatic steatosis are common and increasing health problems among adults in Northeast Germany. Reassuring healthy diet and controlling obesity may result in prevention of above-mentioned health problems.

Effect of Pomegranate Peel Consumption on Liver Enzymes, Lipid Profile, Liver Steatosis, and Hs-CRP in Patients With Non-alcoholic Fatty Liver Disease: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

The most prevalent chronic liver disease for which there is currently no proven treatment is non-alcoholic fatty liver disease (NAFLD). An incomplete understanding of the underlying mechanisms of NAFLD may be the cause. The onset and development of this illness appear to be influenced by problems with lipid metabolism, insulin resistance, oxidative stress, and inflammation. Considering the antioxidant properties of pomegranate peel extract, this study was conducted to determine the effects of pomegranate peel consumption on some metabolic features in patients with NAFLD. Our hypothesis is that pomegranate peel can improve the grade of fatty liver, liver enzymes, lipid profile, serum high-sensitivity C-reactive protein (hs-CRP), and anthropometric indices. The aim of this study was to investigate the efficacy of pomegranate peel extract in NAFLD patients. This double-blind randomized clinical trial was conducted on 46 patients with NAFLD. Patients were randomly assigned to intervention group (n = 23) and placebo group (n = 23). Patients in the pomegranate peel group consumed two capsules, each containing 500 mg pomegranate peel extract daily as a part of low-calorie diet (i.e., 500-deficit calorie diet) for 10 weeks. While patients in the control group followed the low calorie diet and two capsules containing 500 mg maltodextrin. At the beginning and end of the study, demographic information, anthropometric indices, food intake, physical activity level, grade of fatty liver, liver enzymes, lipid profile, and serum high-sensitivity C-reactive protein (hs-CRP) were measured. Food intake was measured by 24-h food recall questionnaires and physical activity was measured by the International Physical Activity Questionnaire (IPAQ). Analysis of food recall questionnaire was done using Nutritionist IV program. Statistical analysis was performed using SPSS software (version 22), and a p value < 0.05 was defined as statistically significant. Of 46 patients, 42 of them completed the trial. At the end of the trial, pomegranate peel group had significantly higher reduction in TG (triglycerides), ALT(alanine aminotransferase), AST(aspartate transferase), hs-CRP and also had higher significant increase in HDL-C(high-density lipoprotein cholesterol) compared to the control group (p = 0/02, p = 0/02, p = 0/01, p = 0/01, and p = 0/04, respectively). However, changes in LDL-C, TC, ALP, GGT, and fatty liver grade were not significantly different between the two groups at the end of the study. The current study indicates that pomegranate peel extract has a favorable effect on liver enzymes, lipid profile, and serum high-sensitivity C-reactive protein (hs-CRP) in patients with NAFLD. To support these results, trials examining various dosages over longer time periods are necessary.

Lincomycin as a growth-promoting antibiotic induces metabolic and immune dysregulation in animals

Since animal growth promoters (AGPs) are used in large quantities and commonly released to the environment from animal farms, it is necessary to determine whether such agents should be regarded as an environmental toxin that poses a threat to the ecosystem and health risk to wildlife. In this study, a multi-omics approach was employed to explore the effects of a representative AGP, lincomycin, on key metabolic and physiological functions of animals, using a mouse model. The results indicated that exposure to lincomycin resulted in a significant increase in growth rate of mice (50.11 %) over an 8 weeks period, during which significant decrease (61.94 %) and increase (68.64 %) in the relative abundance of Firmicutes and Escherichia coli, respectively, was observed in the gut microbiota, indicating that the gut microbiota structure has been altered. Moreover, the mice exhibited altered lipid profiles and liver damage suggestive of early-stage non-alcoholic fatty liver disease (NAFLD). Disruptions in blood glucose and insulin levels associated with type 2 diabetes mellitus (T2DM) were also observed. Furthermore, lincomycin was found to cause suppression in inflammatory responses, as evidenced by the downregulation of related genes and elevated inflammatory mediators, potentially resulting in increased susceptibility to microbial infection. Our findings underscore the detrimental effects of lincomycin on animal health and highlight the necessity for comprehensive toxicological assessments of lincomycin and other AGPs before their environmental release.

Chemogenomic Screening in a Patient-Derived 3D Fatty Liver Disease Model Reveals the CHRM1-TRPM8 Axis as a Novel Module for Targeted Intervention.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver modelfrom primary human hepatocytes and non-parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease-relevant endpoints, such as steatosis, inflammation and fibrosis, and multi-omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls. By combining high-content imaging with scalable biochemical assays and chemogenomic screening, multiple novel targets with anti-steatotic, anti-inflammatory, and anti-fibrotic effects are identified. Among these, activation of the muscarinic M1 receptor (CHRM1) and inhibition of the TRPM8 cation channel result in strong anti-fibrotic effects, which are confirmed using orthogonal genetic assays. Strikingly, using biosensors based on bioluminescence resonance energy transfer, a functional interaction along a novel MASH signaling axis in which CHRM1 inhibits TRPM8 via Gq/11 and phospholipase C-mediated depletion of phosphatidylinositol 4,5-bisphosphate can be demonstrated. Combined, this study presents the first patient-derived 3D MASH model, identifies a novel signaling module with anti-fibrotic effects, and highlights the potential of organotypic culture systems for phenotype-based chemogenomic drug target identification at scale.