Liver Glucose Research Articles

Intermittent fasting, exercise, and dietary modification induce unique transcriptomic signatures of multiple tissues governing metabolic homeostasis during weight loss and rebound weight gain

Obesity and its related metabolic diseases bring great challenges to public health. In-depth understanding on the efficacy of weight-loss interventions is critical for long-term weight control. Our study demonstrated the comparable efficacy of exercise (EX), intermittent fasting (IF), or the change of daily diet from an unhealthy to a normal chow (DR) for weight reduction, but largely divergently affected metabolic status and transcriptome of subcutaneous fat, scapular brown fat, skeletal muscles and liver in high-fat-high-fructose diet (HFHF) induced obese mice. EX and IF reduced systematic inflammation, improved glucose and lipid metabolism in liver and muscle, and amino acid metabolism and thermogenesis in adipose tissues. EX exhibited broad regulatory effects on TCA cycle, carbon metabolism, thermogenesis, propanoate-, fatty acid and amino acid metabolism across multiple tissues. IF prominently affected genes involved in mitophagy and autophagy in adipose tissues and core genes involved in butanoate metabolism in liver. DR, however, failed to improve metabolic homeostasis and biological dysfunctions in obese mice. Notably, by exploring potential inter-organ communication, we identified an obesity-resistant-like gene profile that were strongly correlated with HFHF induced metabolic derangements and could predict the degree of weight regain induced by the follow-up HFHF diet. Among them, 12 genes (e.g., Gdf15, Tfrc, Cdv3, Map2k4, and Nqo1) were causally associated with human metabolic traits, i.e., BMI, body fat mass, HbA1C, fasting glucose, and cholesterol. Our findings provide critical groundwork for improved understanding of the impacts of weight-loss interventions on host metabolism. The identified genes predicting weight regain may be considered regulatory targets for improving long-term weight control.

Xiaozhi formula attenuates non-alcoholic fatty liver disease by regulating lipid metabolism via activation of AMPK and PPAR pathways

BackgroundXiaozhi formula (XZF) is a practical Chinese herbal formula for the treatment of non-alcoholic fatty liver disease (NAFLD), which possesses an authorized patent certificate issued by the State Intellectual Property Office of China (ZL202211392355.0). However, the underlying mechanism by which XZF treats NAFLD remains unclear. PurposeThis study aimed to explore the main component of XZF and its mechanism of action in NAFLD treatment. MethodsUHPLC-Q-Orbitrap HRMS was used to identify the components of the XZF. A high-fat diet (HFD)-induced NAFLD mouse model was used to demonstrate the effectiveness of XZF. Body weight, liver weight, and white fat weight were recorded to evaluate the therapeutic efficacy of XZF. H&E and Oil Red O staining were applied to observe the extent of hepatic steatosis. Liver damage, lipid metabolism, and glucose metabolism were detected by relevant assay kits. Moreover, the intraperitoneal insulin tolerance test and the intraperitoneal glucose tolerance test were employed to evaluate the efficacy of XZF in insulin homeostasis. Hepatocyte oxidative damage markers were detected to assess the efficacy of XZF in preventing oxidative stress. Label-free proteomics was used to investigate the underlying mechanism of XZF in NAFLD. RT-qPCR was used to calculate the expression levels of lipid metabolism genes. Western blot analysis was applied to detect the hepatic protein expression of AMPK, p-AMPK, PPARɑ, CPT1, and PPARγ. Results120 compounds were preliminarily identified from XZF by UHPLC-Q-Orbitrap HRMS. XZF could alleviate HFD-induced obesity, white adipocyte size, lipid accumulation, and hepatic steatosis in mice. Additionally, XZF could normalize glucose levels, improve glucolipid metabolism disorders, and prevent oxidative stress damage induced by HFD. Furthermore, the proteomic analysis showed that the major pathways in fatty acid metabolism and the PPAR signaling pathway were significantly impacted by XZF treatment. The expression levels of several lipolytic and β-oxidation genes were up-regulated, while the expression of fatty acid synthesis genes declined in the HFD + XZF group. Mechanically, XZF treatment enhanced the expression of p-AMPK, PPARɑ, and CPT-1 and suppressed the expression of PPARγ in the livers of NAFLD mice, indicating that XZF could activate the AMPK and PPAR pathways to attenuate NALFD progression. ConclusionXZF could attenuate NAFLD by moderating lipid metabolism by activating AMPK and PPAR signaling pathways.

Dose-dependent alteration in hepatic and cerebral glucose metabolism following exposure to polystyrene microplastic in Wistar rats

Background: Recently, microplastics (MPs) with dimensions less than 5 mm have gained more attention due to their adverse impact on the environment and living creatures. Polystyrene (PS) particle is a key element of primary microplastics, which are causing numerous health issues such as interruption of energy metabolism, oxidative stress, neurotoxicity, immunotoxicity, digestive gland disorders, reproductive disruption, and genotoxicity in marine living organisms. Method: Alteration in carbohydrate metabolism was evaluated in male Wistar rats (six weeks of age) after four weeks of oral exposure to polystyrene microplastic (PS-MP) at three different doses (0.5mg/L, 5mg/L and 50 mg/L via drinking water). Results: Polystyrene exposure caused a significant decrease in blood glucose, liver glycogen, and pyruvic acid content in liver and cerebral tissue. Free amino nitrogen content significantly altered in the liver and cerebrum in a dose-specific manner. The LDH activity was found to be decreased in the liver, whereas it increased in the cerebral cortex of rats in a dose-responsive fashion. Enzymes like glucose 6-phosphatase, GOT, GPT, and succinate dehydrogenase activities demonstrated differential effects on the liver and cerebrum of rats in terms of energy metabolism. Conclusion: It is suggested that sub-acute polystyrene exposure significantly perturbs glucose metabolism by inducing hypoglycemia associated with decreased glycolysis and increased TCA cycle enzyme function in rat liver in a dose-dependent manner. Gluconeogenesis is also affected differentially by metabolic adjustment in the studied organs.

Melatonin increases AKT and SOD gene and protein expressions in diabetic rats

Diabetes mellitus (DM) is a chronic metabolic disease marked by hyperglycemia due to insulin deficiency or insulin resistance leading to many chronic complications. It is thus important to manage diabetes effectively in order to prevent and or delay these complications. Melatonin is produced by the pineal gland and regulates the wake-sleep circadian rhythm. Existing evidence suggests that melatonin may be effective in the management of DM. However, the evidence on the mechanism of the beneficial effect melatonin as a treatment for DM is limited. In this study, we investigated the effect of melatonin treatment on blood glucose, insulin (INS), AKT and superoxide dismutase (SOD) gene levels in diabetic rats. Non-diabetic and diabetic rats were treated orally for 4 weeks with either 25 mg or 50 mg/kg body weight of melatonin. At the end of the study, pancreatic and liver tissues morphology, glucose homeostasis, serum insulin and SOD levels, hepatic gene and protein expression of SOD as protecting antioxidant enzyme and AKT as central element involved in PI3K/AKT insulin signaling pathway were estimated. Melatonin treated diabetic rats showed reduced hyperglycemia, and increased serum insulin and SOD levels. In addition, melatonin induced an increased gene and protein expression of SOD and AKT. In conclusion, melatonin may play a role in treating diabetic rats via stimulation of insulin secretion, insulin signaling and reduction in oxidative stress.

Abstract MP60: A Randomized Placebo-Controlled Trial of Pitavastatin Calcium to Treat Combined Dyslipidemia of Obesity in Adolescents - The Pediatric Heart Network Dyslipidemia of Obesity Intervention in Teens (Do It!) Trial

Background: Combined dyslipidemia of obesity (CDO) is prevalent in ~20% of youth and characterized by high numbers of atherogenic small LDL (sLDL) particles associated with stiffer arteries. The safety and impact of statin therapy is not known. Methods: A 2-year masked trial of pitavastatin calcium 4 mg/day versus placebo for participants ages 10-19 years with body mass index (BMI) ≥85 th %ile and CDO defined as non-HDL-C ≥120 mg/dL and either low HDL-C or high triglyceride (TG):HDL-C ratio. The primary outcome was change in carotid-femoral pulse wave velocity (PWV) and carotid measures assessed at baseline, 6, 12, 18, and 24 months. Secondary outcomes included safety and lipid measures. Results: Across 18 sites, 59 participants were randomized to pitavastatin and 60 to placebo. Demographic (mean age 13.5±1.2 yrs; 55% males), anthropomorphic (BMI %ile 98±3; waist/height ratio 0.66±0.08), lipid (non-HDL-C 167±29 mg/dL, LDL-C 127±25 mg/dL, HDL-C 37±7 mg/dL, TG/HDL ratio 6.4±4.7, sLDL number 866±419 nmol/L), vascular (PWV 5.0±0.7 m/sec) and safety measures were similar at baseline between groups. There were 28 early terminations (11 pitavastatin, 17 placebo). Significant reductions with pitavastatin versus placebo were noted in non-HDL-C (median -25% vs +3% at 6 months, p<0.001), LDL-C (-29% vs +7%, p<0.001), and apolipoprotein B (-26% vs 0%, p<0.001). An early reduction relative to placebo in sLDL particle number was not sustained (FIGURE A), and there were no significant changes or trends for PWV (FIGURE B) or carotid measures in either group. There was one serious adverse event (placebo), and no significant differences in liver enzymes, muscle toxicity, glucose homeostasis, or somatic growth, including adiposity. Conclusions: Over 2 years, treatment of CDO in adolescents with pitavastatin calcium resulted in significant improvement in dyslipidemia with no safety concerns. No change in PWV in either group may be due to lower-than-expected baseline PWV, insufficient magnitude of impact on CDO, or lack of change in adiposity.

Differential Disruption of Glucose and Lipid Metabolism Induced by Phthalates in Human Hepatocytes and White Adipocytes.

Phthalic acid esters (PAEs), commonly used as plasticizers, are pervasive in the environment, leading to widespread human exposure. The association between phthalate exposure and metabolic disorders has been increasingly recognized, yet the precise biological mechanisms are not well-defined. In this study, we explored the effects of monoethylhexyl phthalate (MEHP) and monocyclohexyl phthalate (MCHP) on glucose and lipid metabolism in human hepatocytes and adipocytes. In hepatocytes, MEHP and MCHP were observed to enhance lipid uptake and accumulation in a dose-responsive manner, along with upregulating genes involved in lipid biosynthesis. Transcriptomic analysis indicated a broader impact of MEHP on hepatic gene expression relative to MCHP, but MCHP particularly promoted the expression of the gluconeogenesis key enzymes G6PC and FBP1. In adipocytes, MEHP and MCHP both increased lipid droplet formation, mimicking the effects of the Peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi). Transcriptomic analysis revealed that MEHP predominantly altered fatty acid metabolism pathways in mature adipocytes (MA), whereas MCHP exhibited less impact. Metabolic perturbations from MEHP and MCHP demonstrate shared activation of the PPARs pathway in hepatocytes and adipocytes, but the cell-type discrepancy might be attributed to the differential expression of PPARγ. Our results indicate that MEHP and MCHP disrupt glucose and lipid homeostasis in human liver and adipose through mechanisms that involve the PPAR and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways, highlighting the nuanced cellular responses to these environmental contaminants.

Effects of dietary supplementation with green lentil (Lens culinaris) hulls on NAFLD: Focus on intestinal and hepatic metabolism

Lentil hulls, a by-product of lentil processing, are rich in polyphenols and dietary fiber. In this study, a mouse model of nonalcoholic fatty liver disease (NAFLD) induced by dextran sulfate sodium (DSS) and high-fat diet (HFD) was used to investigate the intervention effect of green lentil hulls (GLH) from the perspective of intestinal and hepatic metabolism. Results suggest that DSS-induced gut inflammation and barrier disruption aggravate NAFLD; GLH intervention lowered body weight, liver weight gain and lipid deposition. It also inhibited liver fat accumulation and inflammation as well as intestinal inflammation. In addition, it enhanced liver antioxidant capacity, glucose tolerance and intestinal barrier integrity. Analysis of intestinal flora indicated that GLH advanced the abundance of Akkermansia-muciniphila and Verrucomicrobiaceae, which led to increased content of short-chain fatty acids (SCFAs) and inhibited the Firmicutes and Proteobacteria. Moreover, GLH intervention regulated taurine and hypotaurine metabolism, as well as the biosynthesis of unsaturated and saturated fatty acids in the liver. The relief by GLH on NAFLD may be a comprehensive effect of its rich dietary fiber and polyphenols on intestinal and hepatic metabolism via the gut-liver axis. This research also suggests that the low-value lentil hulls can serve as a valuable food supplement for enhanced gut health and reduced risk of NAFLD.

Knockdown of ACOT4 alleviates gluconeogenesis and lipid accumulation in hepatocytes

Acyl-CoA thioesterase 4 (ACOT4) has been reported to be related to acetyl-CoA carboxylase activity regulation; However, its exact functions in liver lipid and glucose metabolism are still unclear. Here, we discovered explored the regulatory roles of ACOT4 in hepatic lipid and glucose metabolism in vitro. We found that the expression level of ACOT4 was significantly increased in the hepatic of db/db and ob/ob mice as well as obese mice fed a high fat diet. Adenovirus-mediated overexpression of ACOT4 promoted gluconeogenesis and high-glucose/high-insulin-induced lipid accumulation and impaired insulin sensitivity in primary mouse hepatocytes, whereas ACOT4 knockdown notably suppressed gluconeogenesis and decreased the triglycerides accumulation in hepatocytes. Furthermore, ACOT4 knockdown increased insulin-induced phosphorylation of AKT and GSK-3β in primary mouse hepatocytes. Mechanistically, we found that upregulation of ACOT4 expression inhibited AMP-activated protein kinase (AMPK) activity, and its knockdown had the opposite effect. However, activator A769662 and inhibitor compound C of AMPK suppressed the impact of the change in ACOT4 expression on AMPK activity. Our data indicated that ACOT4 is related to hepatic glucose and lipid metabolism, primarily via the regulation of AMPK activity. In conclusion, ACOT4 is a potential target for the therapy of non-alcoholic fatty liver (NAFLD) and type 2 diabetes.

Mirabegron alleviates fructose induced nonalcoholic fatty liver disease in rats: Insights into the underlying mechanisms

AimNon-alcoholic fatty liver disease (NAFLD) is one of the progressive and chronic disease encompass a range of conditions such as non-alcoholic steatohepatitis (NASH) and cirrhosis. The present study is aimed to elucidate the possible actions of mirabegron, a β3-adrenoreceptor agonist used in the treatment of over active bladder, against NAFLD induced by fructose. Method30 male Wistar rats were randomized into 5 groups (A) Veh, (B) Fru, (C) Fru + Sita, (D) Fru + Mira and (E) Fru + Mira + Resv. Rats of respective groups were treated with mirabegron (10 mg/kg, p.o.), sitagliptin (10 mg/kg, p.o.) and resveratrol (20 mg/kg, p.o.) daily for 14 days. Fructose water was given to all rats to induce NAFLD till end of the study. Simultaneously, biochemical analysis such as glucose, SGOT, SGPT, HDL, LDL, TC and TG were performed to assess the disease progression. In the end of study hepatic biochemistry, SOD, MDA, GSH, inflammatory markers such as TNF-α, IL-1β and Hematoxylin and Eosin (H&E) analysis were performed. Key findingsThe NAFLD rats exhibited a significant weight gain, substantial increase in liver enzymes, glucose, circulating and hepatic total cholesterol, triglycerides, inflammatory cytokines and histological analysis showed hepatic steatosis and inflammation in the Fru group. In contrast, mirabegron alone and in combination with antioxidant provided a promising data on ameliorative effect on hepatic inflammation and steatosis caused by fructose. As a result, mirabegron is found to be a promising therapeutic treatment strategy for NAFLD and its associated complications. SignificanceCollectively, findings in this present study revealed that mirabegron reversed NAFLD by suppressing fructose mediated inflammation, oxidative stress and steatosis.

Comparative effects of pravastatin and rosuvastatin on carbohydrate metabolism in an experimental diabetic rat model.

Statin treatment may increase the risk of diabetes; there is insufficient data on how statins affect glucose regulation and glycemic control and the effects of statins on liver enzymes related to carbohydrate metabolism have not been fully studied. Therefore, we aimed to compare the effects of the statin derivatives, pravastatin, and rosuvastatin, on carbohydrate metabolism in an experimental diabetic rat model. Female Wistar albino rats were used and diabetes was induced by intraperitoneal injection of streptozotocin. Thereafter, 10 and 20 mg kg-1 day-1 doses of both pravastatin and rosuvastatin were administered by oral gavage to the diabetic rats for 8 weeks. At the end of the experiment, body masses, the levels of fasting blood glucose, serum insulin, insulin resistance (HOMA-IR), liver glycogen, and liver enzymes related to carbohydrate metabolism were measured. Both doses of pravastatin significantly in creased the body mass in diabetic rats, however, rosuvastatin, especially at the dose of 20 mg kg-1 day-1 reduced the body mass signi ficantly. Pravastatin, especially at a dose of 20 mg kg-1 day-1, caused significant increases in liver glycogen synthase and glucose 6-phosphate dehydrogenase levels but significant decreases in the levels of glycogen phosphorylase, lactate dehydrogenase, and glucose-6-phosphatase. Hence, pravastatin partially ameliorated the adverse changes in liver enzymes caused by diabetes and, especially at the dose of 20 mg kg-1 day-1, reduced the fasting blood glucose level and increased the liver glycogen content. However, rosuvastatin, especially at the dose of 20 mg kg-1 day-1, significantly reduced the liver glycogen synthase and pyruvate kinase levels, but increased the glycogen phosphorylase level in diabetic rats. Rosuvastatin, 20 mg kg-1 day-1 dose, caused significant decreases in the body mass and the liver glycogen content of diabetic rats. It can be concluded that pravastatin, especially at the dose of 20 mg kg-1 day-1 is more effective in ameliorating the negative effects of diabetes by modulating carbohydrate metabolism.

Safety and Efficacy of Efruxifermin in Combination With a GLP-1 Receptor Agonist in Patients With NASH/MASH and Type 2 Diabetes in a Randomized Phase 2 Study

Background & AimsIn phase 2 studies, efruxifermin, an Fc–FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis (NASH), now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA. MethodsCohort D was a double-blind, placebo-controlled phase 2b study in adults with T2D and MASH with fibrosis (F1–F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters. ResultsAdults (N=31) with T2D and MASH fibrosis (F1–F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (N=21) or placebo (N=10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well tolerated. The most frequent efruxifermin-related adverse events were mild–moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P<.0001 vs placebo) compared to a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA–mediated weight loss. ConclusionsThe tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. Clinicaltrials.gov no. NCT05039450

A Comparative Analysis of Liver Injury Markers in Post-COVID Syndrome among Elderly Patients: A Prospective Study.

In the wake of the global COVID-19 pandemic, understanding its prolonged impact on vulnerable populations has become a critical area of investigation. This study aimed to elucidate the distinctive post-acute sequelae of SARS-CoV-2 infection (PASC) and liver injury in Romania's elderly population, hypothesizing unique demographic, clinical, and healthcare factors influencing the manifestation. A longitudinal design was employed, enrolling COVID-19 patients from the Victor Babes Hospital for Infectious Diseases and Pulmonology in Timisoara, Romania. Participants were stratified into three groups based on age and Long COVID status. The study focused on a variety of demographic, clinical, and biological parameters, including liver function tests, to assess the trajectory and severity of liver injury over six months post discharge. Involving 238 participants, the study revealed a significant increase in the duration of hospitalization for those over 65 (15.8 ± 8.2 days) compared to younger groups (p < 0.001). Notably, elderly Long COVID patients exhibited a marked elevation in liver enzymes post discharge, with median ΔALT and ΔAST of 24.1 U/L and 30.2 U/L, respectively, suggesting ongoing liver injury (p < 0.001). Significant metabolic disruptions were observed, with the ΔFasting glucose showing a substantial median decrease of 21.1 mmol/L in the elderly group (p < 0.001). A pronounced reduction in ΔGGT (16.7 U/L) and ΔLDH (48.7 U/L) was noted, indicating a recovery in liver function and reduced tissue damage (p < 0.001). Coagulation profiles and liver fibrosis risk scores, particularly ΔFIB-4 and ΔAPRI, also significantly improved post discharge, indicating a reduced risk of ongoing liver complications. This study confirms the hypothesis of more severe PASC and liver injury among the elderly Romanian population. Significant improvements post discharge suggest a degree of recovery, yet the persistent alterations in liver enzymes, glucose metabolism, and fibrosis risk scores call for continued monitoring and tailored management strategies.

Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice.

Exercise robustly increases the glucose demands of skeletal muscle. This demand is met by not only muscle glycogenolysis but also accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting hepatic gluconeogenic efficiency and capacity on exercise performance by deleting mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in the liver of mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or postexercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in hepatocytes (double knockout, DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of 2H/1³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. Decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan cross talk during exercise as described by the Cahill and Cori cycles.NEW & NOTEWORTHY Martino and colleagues examined the effects of inhibiting hepatic gluconeogenesis on exercise performance and systemic metabolism during treadmill exercise in mice. Combined inhibition of gluconeogenesis from lactate/pyruvate and alanine impaired exercise endurance and led to hypoglycemia during and after exercise. In contrast, suppressing either pyruvate-mediated or alanine-mediated gluconeogenesis alone had no effect on these parameters. These findings provide new insight into the molecular nodes that coordinate the metabolic responses of muscle and liver during exercise.

Empagliflozin attenuates liver fibrosis in high-fat diet/streptozotocin-induced mice by modulating gut microbiota.

The effects of SGLT2 inhibitors on hepatic fibrosis in diabetes remain unclear. This study aimed to investigate the effects of empagliflozin on liver fibrosis in high-fat diet/streptozotocin-induced mice and the correlation with gut microbiota. After the application of empagliflozin for 6 weeks, we performed oral glucose tolerance and intraperitoneal insulin tolerance tests to assess glucose tolerance and insulin resistance, and stained liver sections to evaluate histochemical and hepatic pathological markers of liver fibrosis. Moreover, 16S rRNA amplicon sequencing was performed on stool samples to explore changes in the composition of intestinal bacteria. We finally analysed the correlation between gut microbiome and liver fibrosis scores or indicators of glucose metabolism. The results showed that empagliflozin intervention improved glucose metabolism and liver function with reduced liver fibrosis, which might be related to changes in intestinal microbiota. In addition, the abundance of intestinal probiotic Lactobacillus increased, while Ruminococcus and Adlercreutzia decreased after empagliflozin treatment, and correlation analysis showed that the changes in microbiota were positively correlated with liver fibrosis and glucose metabolism. Overall, considering the contribution of the gut microbiota in metabolism, empagliflozin might have improved the beneficial balance of intestinal bacteria composition. The present study provides evidence and indicates the involvement of the gut-liver axis by SGLT2 inhibitors in T2DM with liver fibrosis.

Prenatal EGCG consumption impacts hepatic glycogen synthesis and lipid metabolism in adult mice

In this study, the impact of prenatal exposure to Epigallocatechin gallate (EGCG) on the liver of adult offspring mice was investigated. While EGCG is known for its health benefits, its effects of prenatal exposure on the liver remain unclear. Pregnant C57BL/6 J mice were exposed to 1 mg/kg of EGCG for 16 days to assess hepatotoxicity effects of adult offspring. Transcriptomics and metabolomics were employed to elucidate the hepatotoxicity mechanisms. The findings revealed that prenatal EGCG exposure led to a decrease in liver somatic index, enhanced inflammatory responses and disrupted liver function through increased glycogen accumulation in adult mice. The integrated omics analysis revealed significant alterations in key pathways involved in liver glucose lipid metabolism, such as gluconeogenesis, dysregulation of insulin signaling, and induction of liver inflammation. Furthermore, the study found a negative correlation between the promoter methylation levels of Ppara and their mRNA levels, suggesting that EGCG could reduce hepatic lipid content through epigenetic modifications. The findings suggest that prenatal EGCG exposure can have detrimental impacts on the liver among adult individuals and emphasize the need for a comprehensive evaluation of the potential risks associated with EGCG consumption during pregnancy.

Ameliorating the impairment of glucose utilization in a high-fat diet-induced obesity model through the consumption of Tucum-do-Cerrado (Bactris Setosa Mart.).

We evaluated the effect of Tucum-do-Cerrado on glucose metabolism homeostasis and its relationship with redox-inflammatory responses in a high-fat (HF) diet-induced obesity model. The HF diet increased energy intake, feed efficiency, body weight, muscle and hepatic glycogen, insulin, homeostatic model assessment of insulin resistance (HOMA IR) and beta (β)-cell function, and gut catalase (CAT) activity, and decreased food intake, hepatic glutathione reductase (GR), glutathione peroxidase (GPX), glutathione S-transferase (GST), and superoxide dismutase (SOD) activities, hepatic phosphoenolpyruvate carboxykinase 1 (Pck1), and intestinal solute carrier family 5 member 1 (Slc5a1) mRNA levels compared with the control diet. However, the HF diet with Tucum-do-Cerrado decreased hepatic glycogen, and increased hepatic GR activity, hepatic Slc2a2 mRNA levels and serum Tnfa compared with the HF diet. Tucum-do-Cerrado decreased muscle glycogen, intestinal CAT and GPX activities, muscle PFK-1 and HK activities, and increased hepatic protein (CARB) and intestinal lipid (MDA) oxidation, hepatic GST activity, serum antioxidant potential, hepatic phosphofructokinase-1 (PFK-1) activity, intestinal solute carrier family 2 member 2 (Slc2a2), tumor necrosis factor (Tnf), interleukin-1 beta (Il1b), muscle protein kinase AMP-activated alpha 1 (Prkaa1), solute carrier family 2 member 2 (Slc2a2) mRNA levels, and serum interleukin-6 (IL-6) levels, regardless of diet type. Tucum-do-Cerrado consumption may ameliorate impaired glucose utilization in a HF diet-induced obesity model by increasing liver and muscle glucose uptake and oxidation. These data suggest that Tucum-do-Cerrado consumption improves muscle glucose oxidation in non-obese and obese rats. This response may be related to the improvement in the total antioxidant capacity of rats.

High-fat diet induced obesity promotes inflammation, oxidative stress, and hepatotoxicity in female FVB/N mice.

Although obesity and subsequent liver injury are increasingly prevalent in women, female mouse models have generally shown resistance to high-fat diet (HFD)-induced obesity. We evaluated control and HFD-fed male and female FVB/N mice, a strain well-suited to transgenic analyses, for phenotypic, histological, and molecular markers related to control of glucose, lipids, and inflammation in serum, liver, and perigonadal white adipose tissues. Unlike many mouse models, HFD-fed FVB/N females gained more perigonadal and mesenteric fat mass and overall body weight than their male counterparts, with increased hepatic expression of lipogenic PPARγ target genes (Cd36, Fsp27, and Fsp27β), oxidative stress genes and protein (Nqo1 and CYP2E1), inflammatory gene (Mip-2), and the pro-fibrotic gene Pai-1, along with increases in malondialdehyde and serum ALT levels. Further, inherent to females (independently of HFD), hepatic antioxidant heme oxygenase-1 (HMOX1, HO-1) protein levels were reduced compared to their male counterparts. In contrast, males may have been relatively protected from HFD-induced oxidative stress and liver injury by elevated mRNA and protein levels of hepatic antioxidants BHMT and Gpx2, increased fatty acid oxidation genes in liver and adipocytes (Pparδ), despite disorganized and inflamed adipocytes. Thus, female FVB/N mice offer a valuable preclinical, genetically malleable model that recapitulates many of the features of diet-induced obesity and liver damage observed in human females.

Tomatidine ameliorates high-fat-diet/streptozocin (HFD/STZ)-induced type 2 diabetes mellitus in mice

Objective To investigate the effects of tomatidine (Td) on the progression of type 2 diabetes mellitus (T2DM) in mice and uncover the mechanism. Methods T2DM mice model was induced by high-fat diet (HFD) and intrabitoneal injection of streptozotocin (STZ). The mice were grouped as follows: 1, control; 2, T2D; 3, T2D + tomatidine (5 mg/kg); 4, T2D + tomatidine (10 mg/kg); 5, T2D + tomatidine (20 mg/kg). Fasting blood glucose was detected by glucose metre and fasting insulin was detected by the kit to determine the effect of Td on T2DM mice. ELISA, qPCR, and Immunoblot assays were performed to detect the effects of Td on the hepatic glucose homeostasis and inflammation of mice. Immunoblot assays further confirmed the mechanism. Results Td improved blood glucose and insulin resistance in T2DM mice. In addition, Td improved liver function and lipid metabolism disorder in T2DM mice. Td also affected the liver glucose homeostasis related genes in T2DM mice. Td alleviated serum inflammation in T2DM mice. We further found that Td activated AMPK pathway, therefore ameliorating T2DM. Conclusion Td ameliorated HFD/STZ-induced T2DM in mice, suggesting that it could serve as a drug of T2DM.

Effects of Moringa oleifera Leaf Extract on Liver Histopathology: A Systematic Review.

Moringa leaves (Moringa oleifera), which are members of the Moringaceae family, are one of the herbal plants that are widely known in Indonesia. Phytochemical contents of moringa leaf, such as flavonoid, quercetin, and phenolic acid, are believed to have an effect on improvement of NAFLD. Therefore, moringa leaf is considered as one the herbal plants that can be used as supplementation in the form of adjuvant therapy to NAFLD. The study objective of our research is to review the effect of giving moringa leaf to the liver, especially the histopathologic features. This study will be conducted on literature review research design, more specifically in the form of a systematic review. Research Method. Five major electronic web databases, including PubMed, Cochrane Library, Google Scholar, Scopus, and ScienceDirect, were used in identifying literature from 2014 to 2023. From a comprehensive analysis of 13 relevant literature sources, we elucidate the impact of Moringa oleifera leaf extract on liver histopathology, glucose, and lipid metabolism. Furthermore, we provide insights into its safety profile concerning human health. The phytochemical content of Moringa oleifera leaf extract had shown a significant benefit in plant medicinal sector. From the research that had been done, Moringa oleifera leaf extract contributes to give significant improvement on liver histopathological features, glucose, and lipid metabolism on animal sample model.

A Gluconeogenesis-Related Genes Model for Predicting Prognosis, Tumor Microenvironment Infiltration, and Drug Sensitivity in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent malignancy within the digestive system, known for its poor prognosis. Gluconeogenesis, a critical metabolic pathway, is responsible for the synthesis of glucose in the normal liver. This study aimed to examine the role of gluconeogenesis-related genes (GRGs) in HCC and evaluate their impact on the tumor microenvironment infiltration and drug sensitivity in HCC. We retrieved gene expression and clinical pathological data of HCC from The Cancer Genome Atlas (TCGA) database. This dataset was utilized to develop a prognosis model. The data from The International Cancer Genome Consortium (ICGC) served as an independent validation cohort. A least absolute shrinkage and selection operator (LASSO) regression analysis was applied to a curated panel of GRGs to construct and validate the predictive model. Furthermore, unsupervised consensus clustering, based on the expression levels of GRGs, categorized HCC patients into distinct subgroups. A four-gene prognostic model, referred to as GRGs, has been successfully developed with high accuracy and stability for the prediction of HCC patient prognosis. This model enables the stratification of patients into high or low risk groups based on individual risk scores, revealing significant differences in immune infiltration patterns and anti-tumor drug responses. Unsupervised consensus clustering analysis delineated four distinct subgroups of patients, each characterized by a unique prognosis and tumor immune microenvironment (TIME). This study is the first to develop a prognostic model incorporating 4-GRGs that effectively predicts the prognosis, tumor microenvironment infiltration, and drug sensitivity in HCC patients. The model based on 4 GRGs may contribute to predict the prognosis, immunotherapy and chemotherapy response of HCC patients.