Improvement In Hepatic Steatosis Research Articles

6-Gingerol Inhibits De Novo Lipogenesis by Targeting Stearoyl-CoA Desaturase to Alleviate Fructose-Induced Hepatic Steatosis.

Metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), is a worldwide liver disease without definitive or widely used therapeutic drugs in clinical practice. In this study, we confirm that 6-gingerol (6-G), an active ingredient of ginger (Zingiber officinale Roscoe) in traditional Chinese medicine (TCM), can alleviate fructose-induced hepatic steatosis. It was found that 6-G significantly decreased hyperlipidemia caused by high-fructose diets (HFD) in rats, and reversed the increase in hepatic de novo lipogenesis (DNL) and triglyceride (TG) levels induced by HFD, both in vivo and in vitro. Mechanistically, chemical proteomics and cellular thermal shift assay (CETSA)-proteomics approaches revealed that stearoyl-CoA desaturase (SCD) is a direct binding target of 6-G, which was confirmed by further CETSA assay and molecular docking. Meanwhile, it was found that 6-G could not alter SCD expression (in either mRNA or protein levels), but inhibited SCD activity (decreasing the desaturation levels of fatty acids) in HFD-fed rats. Furthermore, SCD deficiency mimicked the ability of 6-G to reduce lipid accumulation in HF-induced HepG2 cells, and impaired the improvement in hepatic steatosis brought about by 6-G treatment in HFD supplemented with oleic acid diet-induced SCD1 knockout mice. Taken together, our present study demonstrated that 6-G inhibits DNL by targeting SCD to alleviate fructose diet-induced hepatic steatosis.

Possible protective effect of natural flavanone naringenin-reduced graphene oxide nanosheets on nonalcoholic fatty liver disease.

Utilizing naringenin as a safe, natural compound for reducing graphene oxide and to determine whether Nar-RGO more effectively mitigates the harmful effects of HFFD-induced NAFLD compared to crude naringenin. Using a straightforward experimental setup, we utilize the bioactive flavonoid naringenin (NAR) as the reducing agent to synthesize naringenin-reduced graphene oxide nanosheets (Nar-RGO). Naringenin loading on graphene oxide was validated using electroscopic methods(SEM and TEM) and zeta potential measurements. Utilization of reduced graphene oxide for naringenin encapsulation resulted in a significant improvement in hepatic steatosis, insulin resistance, oxidative stress, and signs of inflammation in HFFD-induced NAFLD compared to crude naringenin. This study demonstrates that Nar-RGO exhibits significantly greater efficacy compared to free naringenin. Therefore, it can be used as a promising medicine in counteractinghigh-fat-fructose diet (HFFD)-induced NAFLD.

Entamoeba muris mitigates metabolic consequences of high-fat diet in mice

ABSTRACT Metabolic syndrome (MetS) is a cluster of several human conditions including abdominal obesity, hypertension, dyslipidemia, and hyperglycemia, all of which are risk factors of type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). Dietary pattern is a well-recognized MetS risk factor, but additional changes related to the modern Western life-style may also contribute to MetS. Here we hypothesize that the disappearance of amoebas in the gut plays a role in the emergence of MetS in association with dietary changes. Four groups of C57B/6J mice fed with a high-fat diet (HFD) or a normal diet (ND) were colonized or not with Entamoeba muris, a commensal amoeba. Seventy days after inoculation, cecal microbiota, and bile acid compositions were analyzed by high-throughput sequencing of 16S rDNA and mass spectrometry, respectively. Cytokine concentrations were measured in the gut, liver, and mesenteric fat looking for low-grade inflammation. The impact of HFD on liver metabolic dysfunction was explored by Oil Red O staining, triglycerides, cholesterol concentrations, and the expression of genes involved in β-oxidation and lipogenesis. Colonization with E. muris had a beneficial impact, with a reduction in dysbiosis, lower levels of fecal secondary bile acids, and an improvement in hepatic steatosis, arguing for a protective role of commensal amoebas in MetS and more specifically HFD-associated MASLD.

Changes in Transient Elastography with Glucagon-Like Peptide-1 Receptor Agonist Use in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Real-World Retrospective Analysis.

Introduction: Current guidelines recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), especially in patients with comorbid diabetes and obesity. This study investigated the effects of GLP-1RAs on hepatic steatosis and fibrosis in patients with MASLD, as measured by changes in vibration-controlled transient elastography (VCTE) and other clinical parameters in a real-world clinical setting. Methods: We conducted a single-center, retrospective analysis of 96 patients with MASLD from a multidisciplinary care clinic who completed VCTE at baseline and follow-up within 6-24 months to compare changes in controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), as well as other metabolic markers, between GLP-1RA users and nonusers using two-sample t-tests and Wilcoxon rank-sum tests. We also assessed whether improvements in hepatic steatosis, defined as a change in CAP >38 dB/m as previously described in the literature, were associated with improvement in fibrosis. Results: GLP-1RA use resulted in significant improvements in weight (-8.1 kg vs. -3.5 kg, P = 0.009), body mass index (BMI) (-2.9 kg/m2 vs. -1.3 kg/m2, P = 0.012), alanine aminotransferase (-15.0 IU/L vs. -4.0 IU/L, P = 0.017), aspartate aminotransferase (-5.0 IU/L vs. -1.0 IU/L, P = 0.021), glycated hemoglobin (HbA1c) (-0.7% vs. 0.1%, P = 0.019), and CAP (-59.9 dB/m vs. -29.1 dB/m, P = 0.016). Responders also had significant improvements in weight (-9.2 kg vs. -1.9 kg, P < 0.001), BMI (-3.3 kg/m2 vs. -0.7 kg/m2, P < 0.001), diastolic blood pressure (-6.1 mmHg vs. -0.7 mmHg, P = 0.028), HbA1c (-0.8% vs. 0.3%, P < 0.001), and LSM (-1.5 kPa vs. 0.1 kPa, P < 0.001). Conclusions: Patients with MASLD treated with GLP-1RAs showed significant improvements in hepatic steatosis and multiple other metabolic parameters, with weight loss as the proposed mechanism for this liver improvement. In addition, change in CAP >38 dB/m was associated with improvements in LSM and other metabolic parameters, suggesting the clinical utility of VCTE in the surveillance of MASLD.

Indole alleviates nonalcoholic fatty liver disease in an ACE2-dependent manner.

Indole is a microbial metabolite produced by the gut microbiota through the degradation of dietary tryptophan, known for its well-established anti-inflammatory and antioxidant properties. In this study, we collected fecal samples from mice fed a high-fat diet (HFD) and those on a standard diet (SD), then conducted 16S rRNA sequencing to analyze their gut microbiota. The analysis revealed distinct differences in the dominant bacterial species between the two groups, with a significant decrease in indole-producing probiotics in the HFD mice compared to the SD group. Then we administered oral indole treatment to male C57BL/6J mice with HFD-induced NAFLD and observed a significant improvement in hepatic steatosis and inflammation. Notably, indole alleviated the HFD-induced decline in serum Angiotensin-(1-7) [Ang-(1-7)] levels and Angiotensin-Converting Enzyme 2 (ACE2) expression. To further investigate the role of indole and ACE2 in NAFLD, we conducted experiments using ACE2 knockout (ACE2KO) mice that were also induced with HFD-induced NAFLD and treated with indole. Interestingly, the protective effects of indole were compromised in the absence of ACE2. In HepG2 cells, indole similarly stimulated ACE2 expression and, in an ACE2-dependent manner, reduced ROS generation, maintained mitochondrial membrane potential stability, and increased SIRT3 expression. In summary, our results highlight the formation of a biologically active gut-liver axis between the gut microbiota and the liver through the tryptophan metabolite indole, which mitigates NAFLD in an ACE2-dependent manner. Elevating dietary tryptophan and increasing indole levels may represent an effective approach for preventing and treating NAFLD.

Impact of peripheral thyroid hormone balance on liver fat: insights from the NutriAct trial.

Hypothyroidism has been proposed as a potential contributor to steatotic liver disease (SLD), but existing data shows conflicting results in euthyroid subjects. Therefore, we investigated the association between thyroid function and intrahepatic lipids (IHLs) during a 36-month randomized controlled trial evaluating a diet known to reduce liver fat. 502 eligible subjects (aged 50-80 years, ≥1 risk factor for unhealthy aging) were randomly assigned to either follow a diet rich in unsaturated fatty acids, plant protein, and fiber (intervention group, IG), or dietary recommendations of the German Nutrition Society (control group, CG). Serum levels of thyroid hormones (THs) as well as IHLs, defined via magnetic resonance spectroscopy, were measured within an euthyroid subgroup without significant alcohol consumption at baseline (n = 332) and after 12 months (n = 243). A ratio of T3/T4 was used to assess whole-body deiodinase activity. Estimates of glucose and lipid metabolism were analyzed. Only fT3 and T3/T4 ratios showed a significant positive correlation with IHL at baseline. We observed a significant decline in fT3, T3, fT3/fT4 ratio, and T3/T4 ratio in CG and IG after 12 months without significant differences between groups. TSH, fT4, and T4 remained stable. A larger improvement of IHL during dietary intervention was seen in those subjects with a lower decline in T3 concentrations. Altered TH balance indicates a possible compensatory upregulation of whole-body TH activity in subjects with increased liver fat. This might be also relevant during the improvement of hepatic steatosis.

Chronic treatment with glucagon-like peptide-1 and glucagon receptor co-agonist causes weight loss-independent improvements in hepatic steatosis in mice with diet-induced obesity

ObjectivesCo-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice. MethodsMice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice. ResultsDicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance. ConclusionsOur study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions.

The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis

ObjectiveSimultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs – and thus inducing cardiovascular complications – are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models. MethodsIn the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis. ResultsExposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis. ConclusionsOur results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.

Lipidome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys with Metabolic Dysfunction-Associated Steatotic Liver Disease.

Little is known about lipid changes that occur in the setting of metabolic-dysfunction-associated steatotic liver disease (MASLD) regression. We previously reported improvements in hepatic steatosis, de novo lipogenesis (DNL), and metabolomic profiles associated with oxidative stress, inflammation, and selected lipid metabolism in 40 adolescent boys (11-16 y) with hepatic steatosis ≥5% (98% meeting the definition of MASLD). Participants were randomized to a low-free-sugar diet (LFSD) (n = 20) or usual diet (n = 20) for 8 weeks. Here, we employed untargeted/targeted lipidomics to examine lipid adaptations associated with the LFSD and improvement of hepatic steatosis. Our LC-MS/MS analysis revealed decreased triglycerides (TGs), diacylglycerols (DGs), cholesteryl esters (ChE), lysophosphatidylcholine (LPC), and phosphatidylcholine (PC) species with the diet intervention (p < 0.05). Network analysis demonstrated significantly lower levels of palmitate-enriched TG species post-intervention, mirroring the previously shown reduction in DNL in response to the LFSD. Targeted oxylipins analysis revealed a decrease in the abundance of 8-isoprostane and 14,15-DiHET and an increase in 8,9-DiHET (p < 0.05). Overall, we observed reductions in TGs, DGs, ChE, PC, and LPC species among participants in the LFSD group. These same lipids have been associated with MASLD progression; therefore, our findings may indicate normalization of key biological processes, including lipid metabolism, insulin resistance, and lipotoxicity. Additionally, our targeted oxylipins assay revealed novel changes in eicosanoids, suggesting improvements in oxidative stress. Future studies are needed to elucidate the mechanisms of these findings and prospects of these lipids as biomarkers of MASLD regression.

3-(4-Hydroxy-3-methoxyphenyl) propionic acid contributes to improved hepatic lipid metabolism via GPR41

3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) is a metabolite produced by the gut microbiota through the conversion of 4-hydroxy-3-methoxycinnamic acid (HMCA), which is a widely distributed hydroxycinnamic acid-derived metabolite found abundantly in plants. Several beneficial effects of HMPA have been suggested, such as antidiabetic properties, anticancer activities, and cognitive function improvement, in animal models and human studies. However, the intricate molecular mechanisms underlying the bioaccessibility and bioavailability profile following HMPA intake and the substantial modulation of metabolic homeostasis by HMPA require further elucidation. In this study, we effectively identified and characterized HMPA-specific GPR41 receptor, with greater affinity than HMCA. The activation of this receptor plays a crucial role in the anti-obesity effects and improvement of hepatic steatosis by stimulating the lipid catabolism pathway. For the improvement of metabolic disorders, our results provide insights into the development of functional foods, including HMPA, and preventive pharmaceuticals targeting GPR41.

FRI063 Effectiveness Of Liraglutide In Treating Obesity And Improving Hepatic Steatosis

Abstract Disclosure: A.A. Alfadda: None. A. Masood: None. B.M. Alsuwayni: None. A.M. Alhossan: None. Background: Obesity is a chronic relapsing disease with a multifactorial pathology. Chronic inflammation is an important underlying cause, that is also a reason for development of obesity associated comorbidities including metabolic associated fatty liver disease. Medical management of obesity using glucagon-like peptide 1 (GLP-1) agonists has been effective in achieving weight loss and improvements in glucose and lipid control but effects on liver steatosis occurring with persistence of treatment need to be further elucidated. Methods: A single center, prospective study was undertaken to evaluate the effectiveness of liraglutide in patients with obesity. Participants received daily subcutaneous liraglutide with dose escalation (initial dose of 0.6 mg to maximum of 3.0 mg) following the prescribed guidelines. Anthropometric and laboratory parameters were measured at baseline and after three months of receiving the full dose. Estimation of liver steatosis was performed by FibroScan, using controlled attenuation parameter (CAP), and the hepatic steatosis index (HSI) at baseline and at three months of therapy. Descriptive statistics were reported as percentage or mean ± standard deviation (SD) and P values below 0.05 were considered statistically significant. A sub-group analysis was carried out between patients classified as responders to treatment if they lost ≥ 5% of their initial weight, and non-responders, if they did not. Results: In total 28 patients, 18 females (64%) and 10 males (46%) with obesity, mean age 36 ± 11.6 years and BMI (42 ± 4.8) kg/m2, were recruited for the study. Six patients dropped out because of side effects. Twenty-two patients 8 (36.4%) males and 14 (63.6%) females comprised the study population followed for three months. Significant and clinically meaningful changes in weight (decreased by 5.03%), BMI (decreased by 4.71%), HbA1c (decreased by 5.44%), and CAP (decreased by 14.69%) (all P values &amp;lt; 0.05) were noted in all the patients after three months treatment. Sub-group analysis in responders, 16 patients (72.7%), and non-responders 6 patients (27.3%) at three months of treatment demonstrated decrease weight (from 119.64 ± 11.9 to 108.46 ± 11.6 kg; P &amp;lt; 0.001), BMI (from 42.08 ± 5.7 to 38.31 ± 5.7 kg/ m2; P &amp;lt; 0.001), HbA1c (from 5.80 ± 0.4 to 5.38 ± 0.3%; P &amp;lt; 0.001), and CAP (from 286.69 ± 68.6 to 260.69 ± 53.6 dB/m; P = 0.067) in the responders group. On the other hand, we noted a significant decrease in CAP in non-responders’ group (from 285.17 ± 29 to 242.33 ± 51.2; P = 0.041) with no significant changes were observed in anthropometric measures and laboratory markers. Conclusions: Treatment with liraglutide for a period of 3 months in patients with obesity produced significant weight loss and improvement in hepatic steatosis in most patients. Even though the non-responders did not show improvements in weight loss, they demonstrated significant improvements in hepatic steatosis. Presentation: Friday, June 16, 2023

Cystic fibrosis liver disease in the post-modulator era.

Highly effective modulators of cystic fibrosis transmembrane conductance regulator (CFTR) function have had dramatic impact on pulmonary and nutritional outcomes in persons with cystic fibrosis (pwCF). The impact on liver disease in pwCF was not the focus of the registration trials. The purpose of this review is to assess the current literature on the impact of HEMT on liver disease, progression, regression, and safety. Short-term studies of HEMT in pwCF have shown that there is no significant impact on the frequency of liver enzyme abnormalities. There is no evidence for significant improvement in liver enzymes over time on HEMT therapy. There is conflicting data on improvement in liver fibrosis determined by fibrosis indices (APRI and GPR) or elastography. One study showed improvement, and another showed worsening in younger (<20 years old) pwCF. There are reports of resolution or improvement in hepatic steatosis. There are rare reports of severe acute hepatitis and one report of hepatic decompensation leading to liver transplantation due to drug-induced liver disease. HEMT have not been shown to have a significant impact on improving liver disease or preventing fibrosis with short-term therapy. Longer studies are needed to assess the impact of HEMT on liver disease in pwCF.

Solanum lycocarpum St. Hill. fibrous fraction intake can contribute to counteract diet-induced obesity co-morbidities

Solanum lycocarpum St. Hill is a Brazilian Cerrado fruit popularly known as wolf-apple, lobeira or fruta-do-lobo. The proximate composition of fruta-do-lobo showed that the flour prepared from the fruit's pulp has 23g/100g of fiber, which is considered rich in fiber. Data from the literature suggest that dietary fiber intake can positively decrease body weight gain and its adverse side effects through physiological effects and metabolism modulation. From this perspective, this study aimed to analyze the nutritional effects of the fibrous fraction (FF) obtained after extraction of resistant starch from fruta-do-lobo flour in mice with diet-induced obesity. Swiss mice (n = 22) were randomized into three different groups according to the diet offered: control (AIN 93-G diet), HF (high-fat diet – 4% vegetable oil; 31% lard), and FF (HF diet + 3% fibrous fraction of fruta-do-lobo). It was observed that consuming a diet containing the fibrous fraction (FF) promoted histological changes compared to the obese control group (HF) since the liver weight was lower and there was an improvement in hepatic steatosis. Even so, some biological results were observed in the FF group with a profile more similar to the lean control group than the HF group, namely epididymal tissue weight, liver weight, and kITT. It is important to point out that many variables, such as the duration of the protocol and the doses of supplemented dietary fiber, may be associated with the results observed in the present study. However, there is some evidence that the fibrous fraction of fruta-do-lobo can be used as an ingredient to supplement dietary fiber intake and contribute to health promotion.

1571-P: Plasma FGF5 Concentration Correlates Better with Hepatic Steatosis, Blood Glucose, and Specific Plasma Free Fatty Acids than with Other Tissue Fat Accumulation

A few studies reported an association between fibroblast growth factor-5 (FGF5) and NAFLD. We aimed to elucidate the physiologic implication of FGF5 in NAFLD and obesity. A total of 180 subjects [(24 healthy controls and 156 patients with biopsy-proven NAFLD and/or hepatic fat content (HFC) 5% or more on MRI-PDFF] were included to assess association between HFC and various metabolic factors including body fat and plasma levels of glucose, insulin, FGF5, FGF21, oxyntomodulin, incretins, and some free fatty acids (FFAs). Additionally, we analysed a subgroup of obese patients who would undergo laparoscopic sleeve gastrectomy (LSG) (n=50) to see correlation between changes in metabolic variables related to body weight (BW) and HFC before and 6 months after surgery. Plasma FGF5 correlated better with blood glucose and HFC than with total body fat, HOMR-IR, and visceral fat. In relation to plasma FFAs, both FGF5 and HFC together showed a positive correlation with plasma FFAs such as palmitic acid, linolenic acid, and arachidonic acid, but had an inverse correlation with nervonic acid, docosanoic acid, tetracosanoic acid, and hexacosanoic acid. FGF5 level showed an independent association with blood glucose and MRI-PDFF after adjusting for multiple factors. After LSG, BW decreased by an average of 24.6%, while HFC decreased from 19.5% ± 9.1% to 5.7 ± 2.9%, p &amp;lt;0.01). Plasma FGF5 also decreased after LSG (1625.0 ± 656.8 pg/ml vs. 966.8 ± 339.9 pg/ml, p &amp;lt;0.01). The amount of plasma FGF5 change showed a significant correlation with changes in HFC and blood glucose. In conclusion, our results showed that plasma FGF5 level correlated well with HFC, blood glucose, and specific plasma FFAs and also decreased with the improvement of hepatic steatosis after bariatric surgery. Further researches on the causal relationship between FGF5, glucose and lipid metabolism, and NAFLD are needed. Disclosure D.Lee: None. I.Park: None. Funding National Research Foundation of Korea (2021R1A5A2030333, 2019R1I1A2A02062305)

Effects of dietary sugar restriction on hepatic fat in youth with obesity.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children. Like adults, children can develop the progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), which is characterized by hepatic inflammation, often in the presence of fibrosis. Children with NAFLD are at higher risk of liver-related complications, metabolic dysfunction, and cardiovascular disease in adulthood. Many factors contribute to the escalating prevalence of NAFLD in the pediatric population, among which are an array of dietary patterns such as overnutrition, poor diet quality, and heavy consumption of fat and sugar, including fructose. Findings from an increasing number of epidemiological studies support a connection between high habitual sugar consumption and NAFLD, especially within the context of obesity, but these studies are not able to demonstrate whether sugar is a contributing factor or instead an indicator of an overall poor diet (or lifestyle) quality. To date, only four randomized controlled dietary interventions assessing the effects of sucrose/fructose restriction on hepatic fat fraction in youth with obesity have been published. The objectives of this review are to summarize the key findings from these dietary interventions to achieve a better understanding of the strength of the relationship between dietary sugar restriction and liver fat reduction, despite their inherent limitations, and to discuss the potential impact of weight loss and fat mass reduction on improvement in hepatic steatosis.

(397) Long-term Testosterone Therapy in Men with Functional Hypogonadism and Obesity Improves Surrogate Parameters of Liver Function in a Urological Registry Study

Abstract Introduction Hepatic steatosis is highly prevalent in patients with hypogonadism and obesity. Fatty liver is increasingly recognized as cardiovascular risk factor. The gold standard assessment – histological evaluation of liver biopsies – cannot be performed in routine clinical practice. However, the fatty liver index (FLI) can be calculated using the formula by Bedogni: FLI = (e 0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference - 15.745) / (1 + e 0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference - 15.745) * 100 (Bedogni G et al. BMC Gastroenterol 2006;6:33). A FLI &amp;lt;30 rules out and a FLI ≥60 rules in fatty liver. Objective to investigate effects of long-term testosterone therapy (TTh) up to 13 years on surrogate parameters of liver function in men with functional hypogonadism and obesity in comparison to an untreated control group. Methods In an ongoing registry study in men with hypogonadism (total testosterone ≤350 ng/mL and at least moderate symptoms on the Aging Males’ Symptoms scale, AMS) in a single urology office, 491 men had functional hypogonadism and obesity (BMI ≥30 kg/m2). 292 men received testosterone undecanoate (TU) injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 199 opted against TTh and served as controls (CTRL). Height was measured at baseline, weight, waist circumference, triglycerides and γ-GT were assessed at each visit and the fatty liver index (FLI) calculated. AST, ALT, and bilirubin were also measured at each visit. Mean absolute measures with standard deviations (SDs) are reported for a duration of 13 years. Results Mean (median) follow-up: T-group 10.1±3.1 (11), CTRL 9.4±3.3 (10) years. Baseline age was 59.5±6.0 (T-group) and 63.0±5.0 years (CTRL) (p&amp;lt;0.0001). Triglycerides decreased from 3.4±0.5 to 2.2±0.1 in the T-group and increased from 3.2±0.5 to 3.9±0.5 in CTRL (p&amp;lt;0.0001 for both). γ-GT (U/L) decreased from 42.9±22.8 to 20.5±6.4 in the T-group and increased from 35.5±11.6 to 61.7±5.9 in CTRL (p&amp;lt;0.0001 for both). AST (U/L) decreased from 38.4±13.3 to 20.8±1.9 in the T-group and increased from 28.6±9.0 to 54.1±11.9 in CTRL (p&amp;lt;0.0001 for both). ALT (U/L) decreased from 41.4±13.7 to 24.7±2.1 in the T-group and increased from 32.7±9.4 to 60.2±13.8 in CTRL (p&amp;lt;0.0001 for both). Bilirubin decreased from 0.53±0.27 to 0.18±0.05 mg/dL in the T-group and increased from 0.44±0.23 to 1.09±0.27 mg/dL in CTRL (p&amp;lt;0.0001 for both). Waist circumference from 115.0±13.2 to 97.5±4.6 cm in the T-group and increased from 118.6±11.4 to 121.2±6.1 cm in CTRL (p&amp;lt;0.0001 for all). BMI decreased from 36.8±3.6 to 28.3±2.1 kg/m2 in the T-group and increased from 33.9±3.3 to 34.9±2.2 kg/m2 in CTRL (p&amp;lt;0.0001 for all). FLI decreased from 95.1±4.6 to 61.3±11.2 in the T-group and increased from 94.1±4.4 to 98.0±1.3 in CTRL (p&amp;lt;0.0001 for both). Conclusions Long-term testosterone therapy in men with functional hypogonadism and obesity improved surrogate parameters of liver function indicating an improvement in hepatic steatosis. All measures deteriorated over time in untreated obese hypogonadal control patients. Disclosure Yes, this is sponsored by industry/sponsor: Bayer AG, Berlin, Germany. Clarification Industry funding only - investigator initiated and executed study. Any of the authors act as a consultant, employee or shareholder of an industry for: Bayer AG.

Sleeve gastrectomy causes weight-loss independent improvements in hepatic steatosis.

Sleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight-loss independent improvements in liver steatosis in mice with diet-induced obesity (DIO); and to metabolically and transcriptomically profile hepatic changes in mice undergoing VSG. Mice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib). Hepatic steatosis, glucose tolerance, insulin and glucagon resistance, and hepatic transcriptomics were investigated at the end of the study period and treatment groups were compared with mice undergoing sham surgery only (Sham-Ad lib). VSG led to much greater improvement in liver steatosis than Sham-WM (liver triglyceride mg/mg 2.5 ± 0.1, 2.1 ± 0.2, 1.6 ± 0.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.003). Homeostatic model assessment of insulin resistance was improved following VSG only (51.2 ± 8.8, 36.3 ± 5.3, 22.3 ± 6.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.03). The glucagon-alanine index, a measure of glucagon resistance, fell with VSG but was significantly increased in Sham-WM (9.8 ± 1.7, 25.8 ± 4.6 and 5.2 ± 1.2 in Sham Ad-lib, Sham-WM and VSG respectively; p = 0.0003). Genes downstream of glucagon receptor signalling which govern fatty acid synthesis (Acaca, Acacb, Me1, Acly, Fasn and Elovl6) were downregulated following VSG but upregulated in Sham-WM. Changes in glucagon sensitivity may contribute to weight-loss independent improvements in hepatic steatosis following VSG.

The potential of pomegranate peel (&lt;em&gt;Punica granatum&lt;/em&gt;) in the treatment of obese and glucose-intolerant mice

Obesity is a pandemic condition, absolutely out of control. Food assistance is among the main proposals for the management of the disease. Thus, the aim of this study was to evaluate the potential of aqueous pomegranate extract in a model of obesity, glucose intolerance and hepatic steatosis induced by high-fat diet. The pomegranate extract was obtained from the association of green extraction techniques. Through the crude extract containing punicalagin and ellagic acid (main compounds), extracts with isolated fractions of these compounds were obtained. For the experimental study, Swiss mice were subjected to the obesity induction period for eight weeks. After, were treated for another 30 days with crude extract of 250 mg/kg (group HF+[1]EXT); punicalagin extract isolated 8.35 mg/kg (HF+Punica group); isolated extract of ellagic acid 0.208 mg/kg (group HF+EA), via gavage. Both the crude extract and its subfractions reduced the body weight gain for the HF+Punica group (1.1 g); HF+EA (0.92 g) compared to HF, while the HF+EXT showed significant weight loss (P&lt;0.001). In the glycemic parameters, all extracts were able to reduce blood glucose when compared to the group with HF. Histological data of liver tissue showed improvement in hepatic steatosis, mainly in the crude extract group. Therefore, it was possible to demonstrate that the aqueous extract of the pomegranate peel, obtained by innovative extraction techniques, can be a potential strategy for the treatment and control of obesity.&#x0D; &#x0D; [1] abbreviations:EXT – extract, EA- acid ellagic, PUNICA – punicalagin.

An updated meta-analysis of effects of curcumin on metabolic dysfunction-associated fatty liver disease based on available evidence from Iran and Thailand

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common cause of chronic liver disease and can progress to nonalcoholic steatohepatitis and cirrhosis. This study aims to summarize the evidence for the effects of curcumin on MAFLD progression. Studies were identified from Medline and Scopus databases until April 2022. Systematic reviews and meta-analyses (SRMA) and randomized controlled trials (RCT) were selected based on pre-specified criteria. Three reviewers independently extracted data and assessed quality of included studies. Of the 427 identified records, 6 SRMAs and 16 RCTs were included in the analysis. Very high overlap was observed among SRMAs with corrected covered area of 21.9%. From an updated meta-analysis, curcumin demonstrated significant improvement in aspartate and alanine aminotransferase with pooled mean difference [95% confidence interval (CI)] of −3.90 (−5.97, −1.82) and −5.61 (−9.37, −1.85) units/L, respectively. Resolution and improvement of hepatic steatosis was higher in curcumin than control group with pooled relative risk (95% CI) of 3.53 (2.01, 6.22) and 3.41 (1.36, 8.56), respectively. Curcumin supplementation also led to lower fasting blood sugar, body mass index, and total cholesterol. Further trials should be conducted to assess the effect of curcumin on liver histology, especially regarding non-invasive hepatic fibrosis and steatosis.

The potential of pomegranate peel (&lt;em&gt;Punica granatum&lt;/em&gt;) in the treatment of obese and glucose-intolerant mice

Obesity is a pandemic condition, absolutely out of control. Food assistance is among the main proposals for the management of the disease. Thus, the aim of this study was to evaluate the potential of aqueous pomegranate extract in a model of obesity, glucose intolerance and hepatic steatosis induced by high-fat diet. The pomegranate extract was obtained from the association of green extraction techniques. Through the crude extract containing punicalagin and ellagic acid (main compounds), extracts with isolated fractions of these compounds were obtained. For the experimental study, Swiss mice were subjected to the obesity induction period for eight weeks. After, were treated for another 30 days with crude extract of 250 mg/kg (group HF+[1]EXT); punicalagin extract isolated 8.35 mg/kg (HF+Punica group); isolated extract of ellagic acid 0.208 mg/kg (group HF+EA), via gavage. Both the crude extract and its subfractions reduced the body weight gain for the HF+Punica group (1.1 g); HF+EA (0.92 g) compared to HF, while the HF+EXT showed significant weight loss (P&lt;0.001). In the glycemic parameters, all extracts were able to reduce blood glucose when compared to the group with HF. Histological data of liver tissue showed improvement in hepatic steatosis, mainly in the crude extract group. Therefore, it was possible to demonstrate that the aqueous extract of the pomegranate peel, obtained by innovative extraction techniques, can be a potential strategy for the treatment and control of obesity.