Liver Fat Levels Research Articles

Ex Vivo Demonstration of a Novel Dual-Frequency Ultrasound Method for Quantitative Measurements of Liver Fat Content

ObjectiveThe rise in metabolic dysfunction–associated steatotic liver disease prevalence, closely linked with metabolic syndromes and obesity, demands accurate, cost-effective diagnostic methods for early-stage fat quantification in the liver. Here we demonstrate a novel dual-frequency ultrasound method that enables the quantitative measurement of liver fat fraction ex vivo and its correlation with actual fat content. MethodsA total of 24 Wistar rats were divided into four different groups, where three groups were given a high-fat diet for 2, 4, and 6 wk, and the last group was given a control diet for 6 wk. Livers were imaged with ultrasound ex vivo in a water bath with a dual-frequency ultrasound transducer and experimental imaging protocol implemented on the Verasonics Vantage research ultrasound scanner. Ultrasound data were post-processed to estimate the non-linear bulk elasticity parameter and the liver samples were analyzed with respect to fat fraction and triglycerides. ResultsRats given a high-fat diet had increased mean levels of liver fat compared with the control group. More importantly, correlation between the ultrasound-based estimation of the non-linear bulk elasticity parameter and fat fraction and triglycerides on an individual level was found to be strong (R2 = 0.81, p = 5.8 × 10-9 and R2 = 0.72, p = 3.6 × 10-7, respectively). ConclusionThis study demonstrates the potential of the novel dual-frequency ultrasound method for the quantitative measurement of liver fat fraction in excised rat livers, showing great promise for this method to become clinically relevant in the diagnosis and follow-up of patients with fatty liver disease.

Olanzapine Induces Adipogenesis and Glucose Uptake by Activating Glycolysis and Synergizing with the PI3K-AKT Pathway.

Administration of olanzapine (OLA) is closely associated with obesity and glycolipid abnormalities in patients with schizophrenia (SCZ), although the exact molecular mecha- nisms remain elusive. We conducted comprehensive animal and molecular experiments to elucidate the mecha- nisms underlying OLA-induced weight gain. We investigated the mechanisms of OLA-induced adipogenesis and lipid storage by em- ploying a real-time ATP production rate assay, glucose uptake test, and reactive oxygen species (ROS) detection in 3T3-L1 cells and AMSCs. Rodent models were treated with OLA using various interven- tion durations, dietary patterns (normal diets/western diets), and drug doses. We assessed body weight, epididymal and liver fat levels, and metabolic markers in both male and female mice. OLA accelerates adipogenesis by directly activating glycolysis and its downstream PI3K sig- naling pathway in differentiated adipocytes. OLA promotes glucose uptake in differentiated 3T3-L1 preadipocytes. In mouse models with normal glycolipid metabolism, OLA administration failed to in- crease food intake and weight gain despite elevated GAPDH expression, a marker related to glycolysis and PI3K-AKT. This supports the notion that glycolysis plays a significant role in OLA-induced met- abolic dysfunction. OLA induces glycolysis and activates the downstream PI3K-AKT signaling pathway, thereby promoting adipogenesis.

Association between liver fat level and risk of hypertension: evidence from a Chinese health examination dataset.

Hypertension development is predominantly influenced by inflammation, excessive fat deposition, and metabolic irregularities. Among these factors, liver fat accumulation is a critical metabolic disorder. However, the quantification of liver fat levels and its associated risk for hypertension incidence remain ambiguous. This project is designed to explore the association between liver fat levels and the risk of hypertension in a healthy population. This cross-sectional study involved 4955 participants from the Health Management Center at Henan Provincial People's Hospital who were surveyed between February 2020 and February 2023. Participants were categorized into four groups based on liver fat quartiles. Subgroup analyses, restricted cubic spline regression models, and logistic regression were utilized to assess the association between liver fat levels and hypertension risk. The relationships between liver fat levels and inflammatory markers were examined using multiple linear regression models. Additionally, a mediation analysis was conducted to explore the role of inflammatory factors in the relationship between liver fat and hypertension risk. Participants with hypertension exhibited greater liver fat levels than did those without hypertension. An increased risk of hypertension was associated with elevated liver fat levels, even after adjusting for other covariates [Q4 vs. Q1 in model II: odds ratio (OR = 1.28), 95% confidence interval (CI) = 1.04-1.59, P = 0.022; P for trend = 0.039]. A nonlinear relationship was observed between liver fat level and hypertension risk, with a notable increase in hypertension risk occurring at liver fat levels greater than 8.65%. Additionally, a positive correlation was found between inflammatory markers and liver fat levels. A mediation effect of 4.76% was noted, linking hypertension risk and liver fat levels through neutrophils. Liver fat levels exceeding 8.65% significantly elevated the risk of hypertension. Inflammatory factors serve as crucial mediators of the relationship between liver fat and hypertension.

MAVMET trial: maraviroc and/or metformin for metabolic dysfunction associated fatty liver disease in adults with suppressed HIV.

Metabolic dysfunction associated fatty liver disease (MAFLD) is over-represented in people with HIV (PWH). Maraviroc (MVC) and/or metformin (MET) may reduce MAFLD by influencing inflammatory pathways and fatty acid metabolism. Open-label, 48-week randomized trial with a 2 x 2 factorial design. Multicenter HIV clinics. Nondiabetic, virologically suppressed PLWH, aged at least 35 years, with confirmed/suspected MAFLD (≥1 biochemical/anthropometric/radiological/histological features). Adjunctive MVC; MET; MVC+MET vs. antiretroviral therapy (ART) alone. Change in liver fat fraction (LFF) between baseline and week-48 using magnetic resonance proton density fat fraction (MR PDFF). Six sites enrolled 90 participants (93% male; 81% white; median age 52 [interquartile range, IQR 47-57] years) between March 19, 2018, and November 11, 2019. Seventy percent had imaging/biopsy and at least one 1 MAFLD criteria. The analysis included 82/90 with week-0 and week-48 scans. Median baseline MR PDFF was 8.9 (4.6-17.1); 40, 38, 8, and 14% had grade zero, one, two, and three steatosis, respectively. Mean LFF increased slightly between baseline and follow-up scans: 2.22% MVC, 1.26% MET, 0.81% MVC+MET, and 1.39% ART alone. Prolonged intervention exposure (delayed week-48 scans) exhibited greater increases in MR PDFF (estimated difference 4.23% [95% confidence interval, 95% CI 2.97-5.48], P < 0.001). There were no differences in predicted change for any intervention compared to ART alone: MVC (-0.42% [95% CI -1.53 to 0.68, P = 0.45]), MET (-0.62 [-1.81 to 0.56, P = 0.30]), and MVC+MET (-1.04 [-2.74 to 0.65, P = 0.23]). Steatosis grade remained unchanged in 55% and increased in 24%. Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET, or the combination significantly reduced liver fat as measured by MRPDFF compared to ART alone.

Determinants of plasma levels of proglucagon and the metabolic impact of glucagon receptor signalling: a UK Biobank study

Aims/hypothesesGlucagon and glucagon-like peptide-1 (GLP-1) are derived from the same precursor; proglucagon, and dual agonists of their receptors are currently being explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated levels of endogenous glucagon (hyperglucagonaemia) have been linked with hyperglycaemia in individuals with type 2 diabetes but are also observed in individuals with obesity and MASLD. GLP-1 levels have been reported to be largely unaffected or even reduced in similar conditions. We investigated potential determinants of plasma proglucagon and associations of glucagon receptor signalling with metabolic diseases based on data from the UK Biobank.MethodsWe used exome sequencing data from the UK Biobank for ~410,000 white participants to identify glucagon receptor variants and grouped them based on their known or predicted signalling. Data on plasma levels of proglucagon estimated using Olink technology were available for a subset of the cohort (~40,000). We determined associations of glucagon receptor variants and proglucagon with BMI, type 2 diabetes and liver fat (quantified by liver MRI) and performed survival analyses to investigate if elevated proglucagon predicts type 2 diabetes development.ResultsObesity, MASLD and type 2 diabetes were associated with elevated plasma levels of proglucagon independently of each other. Baseline proglucagon levels were associated with the risk of type 2 diabetes development over a 14 year follow-up period (HR 1.13; 95% CI 1.09, 1.17; n=1562; p=1.3×10−12). This association was of the same magnitude across strata of BMI. Carriers of glucagon receptor variants with reduced cAMP signalling had elevated levels of proglucagon (β 0.847; 95% CI 0.04, 1.66; n=17; p=0.04), and carriers of variants with a predicted frameshift mutation had higher levels of liver fat compared with the wild-type reference group (β 0.504; 95% CI 0.03, 0.98; n=11; p=0.04).Conclusions/interpretationOur findings support the suggestion that glucagon receptor signalling is involved in MASLD, that plasma levels of proglucagon are linked to the risk of type 2 diabetes development, and that proglucagon levels are influenced by genetic variation in the glucagon receptor, obesity, type 2 diabetes and MASLD. Determining the molecular signalling pathways downstream of glucagon receptor activation may guide the development of biased GLP-1/glucagon co-agonist with improved metabolic benefits.Data availabilityAll coding is available through https://github.com/nicwin98/UK-Biobank-GCGGraphical

Bidirectional two-sample mendelian randomization analysis identifies causal associations of MRI-based cortical thickness and surface area relation to NAFLD

BackgroundNon-alcoholic fatty liver disease (NAFLD) patients have exhibited extra-hepatic neurological changes, but the causes and mechanisms remain unclear. This study investigates the causal effect of NAFLD on cortical structure through bidirectional two-sample Mendelian randomization analysis.MethodsGenetic data from 778,614 European individuals across four NAFLD studies were used to determine genetically predicted NAFLD. Abdominal MRI scans from 32,860 UK Biobank participants were utilized to evaluate genetically predicted liver fat and volume. Data from the ENIGMA Consortium, comprising 51,665 patients, were used to evaluate the associations between genetic susceptibility, NAFLD risk, liver fat, liver volume, and alterations in cortical thickness (TH) and surface area (SA). Inverse-variance weighted (IVW) estimation, Cochran Q, and MR-Egger were employed to assess heterogeneity and pleiotropy.ResultsOverall, NAFLD did not significantly affect cortical SA or TH. However, potential associations were noted under global weighting, relating heightened NAFLD risk to reduced parahippocampal SA and decreased cortical TH in the caudal middle frontal, cuneus, lingual, and parstriangularis regions. Liver fat and volume also influenced the cortical structure of certain regions, although no Bonferroni-adjusted p-values reached significance. Two-step MR analysis revealed that liver fat, AST, and LDL levels mediated the impact of NAFLD on cortical structure. Multivariable MR analysis suggested that the impact of NAFLD on the cortical TH of lingual and parstriangularis was independent of BMI, obesity, hyperlipidemia, and diabetes.ConclusionThis study provides evidence that NAFLD causally influences the cortical structure of the brain, suggesting the existence of a liver-brain axis in the development of NAFLD.

Plasma IGFBP-2 levels reveal heterogeneity in hepatic fat content in adults with excess visceral adiposity.

Obesity is frequently accompanied by a fatty liver. However, some individuals with high abdominal fat levels nevertheless have low levels of liver fat. Reasons for such discordant phenotypes are unclear. In this paper, we report that among asymptomatic individuals with high levels of visceral fat, low concentrations of IGFBP-2 in the circulation were associated with significantly higher hepatic fat content compared to those with high IGFBP-2 levels. We conclude that quantification of plasma IGFBP-2 concentrations may be useful to identify the early risk for liver fat accumulation in apparently healthy individuals without cardiovascular symptoms. Although excess visceral adiposity (VAT) is generally associated with increased liver fat (LF), recent evidence has revealed heterogeneity in LF content among adults with visceral obesity, potentially contributing to specific differences in cardiometabolic outcomes. Reasons for such discordant VAT-LF phenotypes are largely unknown. The present study aimed at assessing whether circulating levels of insulin growth-factor binding protein-2 (IGFBP-2) could be a useful biomarker in the identification of heterogenous and discordant VAT-LF phenotypes. A sample of 308 middle-aged Caucasian apparently healthy men and women without cardiovascular symptoms were studied for the present cross-sectional analyses. Fasting plasma glucose and lipid levels were assessed and an oral glucose tolerance test was performed. Hepatic fat fraction (HFF) was measured using magnetic resonance spectroscopy whereas VAT was assessed by magnetic resonance imaging. Plasma IGFBP-2 levels were quantified by ELISA. Participants were then classified on the basis of median VAT (81 mL) and IGFBP-2 levels (233 ng/mL). Individuals with high levels of VAT were characterized by higher waist circumference, lower insulin sensitivity, as well as by higher plasma triglyceride and lower HDL-cholesterol levels. Plasma IGFBP-2 levels were inversely correlated with HFF (r = -0.39, p < 0.0001). Among men and women with high levels of VAT, those with low levels of IGFBP-2 had significantly higher HFF (7.5 ± 0.7%), compared to participants with high IGFBP-2 concentrations (3.2 ± 0.5%, p < 0.0001). In the presence of excess VAT, high IGFBP-2 concentrations are associated with low levels of LF. Although additional studies will be necessary to establish causality and further clarify the clinical implications of these observations, these findings are concordant with a novel function of IGFBP-2 in modulating susceptibility to non-alcoholic fatty liver disease (NAFLD) in the presence of visceral obesity.

The effects of GLP-1 receptor agonists on visceral fat and liver ectopic fat in an adult population with or without diabetes and nonalcoholic fatty liver disease: A systematic review and meta-analysis.

To uncover the effect of GLP-1 receptor agonists (GLP-1 RAs) on the visceral- and hepatic fat content of adults. PubMed, EMBASE, Cochrane Library, and Web of Science were searched from inception until November 2022. Randomized controlled trials (RCTs) of GLP-1Ras was extracted, including reports of effects on visceral adipose tissue and hepatic fat content in individuals with type 2 diabetes, non-type 2 diabetes, NAFLD (non-alcoholic fatty liver disease), and non-NAFLD. Meta-analyses used random-effects models. 1736 individuals in the 30 qualified RCTs were included, comprising 1363 people with type 2 diabetes and 318 with NFLD. GLP-1 RAs reduced visceral adipose tissue (standard mean difference [SMD] = -0.59, 95% CI [-0.83, -0.36], P<0.00001) and hepatic fat content (weighted mean difference [WMD] = -3.09, 95% CI [-4.16, -2.02], P<0.00001) compared to other control treatment. Subgroup analysis showed that GLP-1Ras dramatically decreased visceral fat in patients with type 2 diabetes (SMD = -0.49, 95% CI [-0.69, -0.29] P<0.00001), NAFLD (SMD = -0.99, 95% CI [-1.64, -0.34] P = 0.003), non-type 2 diabetes (SMD = -1.38, 95% CI [-2.44, -0.32] P = 0.01), and non-NAFLD (SMD = -0.53, 95% CI [-0.78, -0.28] P<0.0001). GLP-1Ras reduced the liver fat level of type 2 diabetes (WMD = -3.15, 95% CI [-4.14, -2.15] P<0.00001), NAFLD (WMD = -3.83, 95% CI [-6.30, -1.37] P = 0.002), and type 2 diabetes with NAFLD (WMD = -4.27, 95% CI [-6.80, -1.74] P = 0.0009), while showed no impact on the hepatic fat content in non-Type 2 diabetes (WMD = -12.48, 95% CI [-45.19, 20.24] P = 0.45). LP-1 RAs significantly reduce visceral- and liver fat content in adults.

Effect of Jinlida granule on glycolipid metabolism, oxidative stress, and inflammatory factors in type 2 diabetes mellitus patients with non alcoholic fatty liver disease

Purpose: To investigate the effect of Jinlida granule on glycolipid metabolism, oxidative stress, and inflammatory factors in type 2 diabetes mellitus (T2DM) patients with non-alcoholic fatty liver disease (NAFLD). Methods: A total of 132 T2DM patients with NAFLD were equally and randomly divided into study and control groups. Patients in the control group were treated with non-drug therapy including routine diet control, exercise, alcohol avoidance, and drug therapy (using blood glucose and lipid lowering drugs). The study group was treated with Jinlida granule in addition to other measures used in the control group. Blood glucose, blood lipid, and liver function parameters were compared after treatment. Nesfatin-1, oxidative stress, inflammatory factors, liver fat content, and degree of fibrosis were assessed. The efficacy and potential mechanism of Jinlida granule in the patients were assessed. Results: Blood glucose, lipid, and liver function parameters in the study group were lower than in the control group following treatment. Nesfatin-1, GSH-Px, and adiponectin levels were higher, while MDA, TNF-α, liver fat, LSM and CAP levels were lower than in the control group (p &lt; 0.05). The response rate of the study group was 96.97 %, which was higher than the 87.88 % in the control group (p &lt; 0.05). The incidence of adverse drug reactions in the two groups during treatment was comparable (p &gt; 0.05). Conclusion: Jinlida granule exerts positive effect on T2DM patients with NAFLD. Thus, Jinlida granule has potentials for application as an adjuvant in the treatment of T2DM with NAFLD.

Abstract P621: Visceral Adipose Tissue Attenuation: A Marker of Liver Fat Content Beyond the Body Mass Index and Visceral Adipose Tissue Area

Introduction: Body mass index (BMI) and visceral adiposity cannot fully discriminate individuals at risk of presenting non-alcoholic fatty liver. Discordant visceral adiposity/liver fat phenotypes highlight the need for a better understanding of mechanisms involved in liver fat (LF) accumulation independent of BMI and visceral adipose tissue (VAT) quantity. Hypothesis: As VAT attenuation is a marker of VAT quality, we hypothesized that this marker would be an important determinant of LF accumulation and that a lower VAT attenuation would be associated with an increased LF accumulation irrespective of BMI and VAT area. Methods: Analyses included 3002 participants (51% men) aged 40 to 70 years with BMI values between 18.5 and 40.0 kg/m 2 of INSPIRE ME-IAA, a prospective observational study conducted in 29 countries in America, Asia, and Europe. Computed tomography was used to measure subcutaneous adipose tissue (SAT) and VAT area and attenuation (a marker of adipocyte size) and liver attenuation (a marker of LF content). Participants’ cardiometabolic health profile was assessed in the fasting state. Partial Pearson correlation coefficients were computed to document the associations between VAT area and attenuation and liver attenuation. Multivariable regression analyses were performed to quantify the contribution of SAT and VAT area and attenuation to LF attenuation. A mixed-model ANOVA was used to compare liver attenuation according to VAT area and attenuation, and to compare VAT attenuation according to LF level and VAT area. A generalized linear mixed model was used to compare the prevalence of type 2 diabetes according to LF content and VAT area. Results: VAT attenuation was associated with liver attenuation in women (r=0.34, p&lt;0.0001; r=0.38, p&lt;0.0001; r=0.36, p&lt;0.0001) and men (r=0.42, p&lt;0.0001; r=0.30, p&lt;0.0001; r=0.24, p&lt;0.0001) within each BMI category (normal weight, overweight, obesity), respectively. VAT attenuation better explained LF attenuation than SAT and VAT area. A low VAT attenuation was associated with a lower liver attenuation within each VAT area tertile in all BMI categories (p&lt;0.05). Furthermore, an increased LF content was associated with a lower VAT attenuation (p&lt;0.05) independent of SAT and VAT area in both sexes in all BMI categories. An increased LF content was also associated with a higher prevalence of type 2 diabetes (p&lt;0.05) in individuals with normal weight and overweight beyond VAT area. Conclusion: A low VAT attenuation reflecting larger adipocytes is associated with an increased LF content and risk of type 2 diabetes independent of BMI and VAT area. These results suggest that VAT attenuation as a marker of adipose tissue quality might be involved in the development of non-alcoholic fatty liver disease.

Physical activity is inversely associated with hepatic fibro-inflammation: A population-based cohort study using UK Biobank data

Physical activity (PA) is recommended in the management of non-alcoholic fatty liver disease (NAFLD) given its beneficial effects on liver fat and cardiometabolic risk. Using data from the UK Biobank population-cohort, this study examined associations between habitual PA and hepatic fibro-inflammation. A total of 840 men and women aged 55-70 years were included in this cross-sectional study. Hepatic fibro-inflammation (iron-corrected T1 [cT1]) and liver fat were measured using MRI, whilst body fat was measured using dual-energy X-ray absorptiometry. PA was measured using accelerometry. Generalised linear models examined associations between PA (light [LPA], moderate [MPA], vigorous [VPA], moderate-to-vigorous [MVPA] and mean acceleration) and hepatic cT1. Models were fitted for the whole sample and separately for upper and lower median groups for body and liver fat. Models were adjusted for sociodemographic and lifestyle variables. In the full sample, LPA (-0.08ms [-0.12 to -0.03]), MPA, (-0.13ms [-0.21 to -0.05]), VPA (-1.16ms [-1.81 to -0.51]), MVPA (-0.14ms [-0.21 to -0.06]) and mean acceleration (-0.67ms [-1.05 to-0.28]) were inversely associated with hepatic cT1. With the sample split by median liver or body fat, only VPA was inversely associated with hepatic cT1 in the upper median groups for body (-2.68ms [-4.24 to -1.13]) and liver fat (-2.33 [-3.73 to -0.93]). PA was unrelated to hepatic cT1 in the lower median groups. Within a population-based cohort, device-measured PA is inversely associated with hepatic fibro-inflammation. This relationship is strongest with VPA and is greater in people with higher levels of body and liver fat. This study has shown that people who regularly perform greater amounts of physical activity have a reduced level of inflammation and fibrosis in their liver. This beneficial relationship is particularly strong when more intense physical activity is undertaken (i.e., vigorous-intensity), and is most visible in individuals with higher levels of liver fat and body fat.

Levels of abdominal adipose tissue and metabolic-associated fatty liver disease (MAFLD) in middle age according to average fast-food intake over the preceding 25 years: the CARDIA Study

Higher levels of intra-abdominal adipose tissue (IAAT) comprising visceral adipose tissue (VAT), intermuscular adipose tissue (IMAT), and liver fat are posited drivers of obesity-related chronic disease risk. Fast food is hypothesized to contribute to IAAT patterns. We quantified levels of abdominal subcutaneous adipose tissue (SAT), IAAT, and odds of metabolic-associated fatty liver disease (MAFLD) in middle age according to average fast-food intake over the preceding 25 y. We analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants underwent 6 clinical exams and measurements over 25 y with computed tomography-measured VAT, SAT, and IMAT (n=3156), plus MAFLD defined by liver attenuation (≤40 Hounsfield units) and 1metabolic abnormality at year 25 (2010, n=3001, n cases=302). We estimated means of VAT, SAT, IMAT, and liver attenuation at the year 25 exam according to categories of average fast-food intake over the previous 25 y adjusted for sociodemographic and lifestyle factors and logistic regression to estimate the odds ratio of MAFLD at year 25. With higher average fast-food intake over 25 y (categorized as follows: never-1×/mo, >1×-3×/mo, 1-<2×/wk, 2-<3×/wk, ≥3×/wk), there were monotonic higher levels of VAT (98.5, 127.6, 134.5, 142.0, 145.5 cm3), P-trend<0.0001, which were consistent across anthropometrically classified obesity categories. There was a similar pattern with liver fat. There were higher levels of IMAT and SAT with higher fast-food intake (P-trend=0.003, 0.0002, respectively), with amounts leveling off at≥2×/wk. In addition, compared with participants who ate fast food never-1×/mo, there were monotonic higher odds of having MAFLD at year 25 with higher average fast-food intake, with participants who ate fast food≥3×/wk having an OR of MAFLD=5.18 (95% CI: 2.87, 9.37). There were monotonic higher levels of VAT, liver fat, and odds of having MAFLD in middle age according to higher average fast-food intake over the preceding 25 y.

Extra virgin coconut oil (Cocos nucifera L.) exerts anti-obesity effect by modulating adiposity and improves hepatic lipid metabolism, leptin and insulin resistance in diet-induced obese rats

Few studies have addressed the effect of extra virgin coconut oil (E-VCO) in obesity. Therefore, this study investigated the anti-adiposity effect of E-VCO focusing on biochemical parameters and liver health of obese rats. E-VCO contains caprilyc, capric and lauric fatty acids and rutin, 3,4-dihydroxybenzoic acid, salicylic acid as major phenolic compounds. A total of 32 male Wistar rats were randomized into four groups: healthy; healthy treated with E-VCO; obese; obese treated with E-VCO. The rats consumed a control or cafeteria diet for 16 weeks. The treated groups received 3,000 mg/kg of E-VCO via gavage. E-VCO reduced body mass and adiposity index and improved hormonal parameters. E-VCO also decreased the accumulation of liver fat, hepatic cholesterol and triglyceride levels, increased faecal cholesterol excretion and decreased faecal triglycerides excretion. E-VCO had an anti-adiposity effect and reversed changes in liver and adipose tissues induced by obesity with improvements in metabolic parameters.

Breastfeeding may benefit cardiometabolic health of children exposed to increased gestational glycemia in utero.

There is altered breastmilk composition among mothers with gestational diabetes and conflicting evidence on whether breastfeeding is beneficial or detrimental to their offspring's cardiometabolic health. We aimed to investigate associations between breastfeeding and offspring's cardiometabolic health across the range of gestational glycemia. We included 827 naturally conceived, term singletons from a prospective mother-child cohort. We measured gestational (26-28weeks) fasting plasma glucose (FPG) and 2-h plasma glucose (2hPG) after an oral glucose tolerance test as continuous variables. Participants were classified into 2 breastfeeding categories (high/intermediate vs. low) according to their breastfeeding duration and exclusivity. Main outcome measures included magnetic resonance imaging (MRI)-measured abdominal fat, intramyocellular lipids (IMCL), and liver fat, quantitative magnetic resonance (QMR)-measured body fat mass, blood pressure, blood lipids, and insulin resistance at 6years old (all continuous variables). We evaluated if gestational glycemia (FPG and 2hPG) modified the association of breastfeeding with offspring outcomes after adjusting for confounders using a multiple linear regression model that included a 'gestational glycemia × breastfeeding' interaction term. With increasing gestational FPG, high/intermediate (vs. low) breastfeeding was associated with lower levels of IMCL (p-interaction = 0.047), liver fat (p-interaction = 0.033), and triglycerides (p-interaction = 0.007), after adjusting for confounders. Specifically, at 2 standard deviations above the mean gestational FPG level, high/intermediate (vs. low) breastfeeding was linked to lower adjusted mean IMCL [0.39% of water signal (0.29, 0.50) vs. 0.54% of water signal (0.46, 0.62)], liver fat [0.39% by weight (0.20, 0.58) vs. 0.72% by weight (0.59, 0.85)], and triglycerides [0.62mmol/L (0.51, 0.72) vs. 0.86mmol/L (0.75, 0.97)]. 2hPG did not significantly modify the association between breastfeeding and childhood cardiometabolic risk. Our findings suggest breastfeeding may confer protection against adverse fat partitioning and higher triglyceride concentration among children exposed to increased glycemia in utero.

Machine learning enables new insights into genetic contributions to liver fat accumulation

Excess liver fat, called hepatic steatosis, is a leading risk factor for end-stage liver disease and cardiometabolic diseases but often remains undiagnosed in clinical practice because of the need for direct imaging assessments. We developed an abdominal MRI-based machine-learning algorithm to accurately estimate liver fat (correlation coefficients, 0.97-0.99) from a truth dataset of 4,511 middle-aged UK Biobank participants, enabling quantification in 32,192 additional individuals. 17% of participants had predicted liver fat levels indicative of steatosis, and liver fat could not have been reliably estimated based on clinical factors such as BMI. A genome-wide association study of common genetic variants and liver fat replicated three known associations and identified five newly associated variants in or near the MTARC1, ADH1B, TRIB1, GPAM, and MAST3 genes (p < 3 × 10-8). A polygenic score integrating these eight genetic variants was strongly associated with future risk of chronic liver disease (hazard ratio > 1.32 per SD score, p < 9 × 10-17). Rare inactivating variants in the APOB or MTTP genes were identified in 0.8% of individuals with steatosis and conferred more than 6-fold risk (p < 2 × 10-5), highlighting a molecular subtype of hepatic steatosis characterized by defective secretion of apolipoprotein B-containing lipoproteins. We demonstrate that our imaging-based machine-learning model accurately estimates liver fat and may be useful in epidemiological and genetic studies of hepatic steatosis.

Non-invasive methods for imaging hepatic steatosis and their clinical importance in NAFLD.

Hepatic steatosis is a key histological feature of nonalcoholic fatty liver disease (NAFLD). The non-invasive quantification of liver fat is now possible due to advances in imaging modalities. Emerging data suggest that high levels of liver fat and its temporal change, as measured by quantitative non-invasive methods, might be associated with NAFLD progression. Ultrasound-based modalities have moderate diagnostic accuracy for liver fat content and are suitable for screening. However, of the non-invasive imaging modalities, MRI-derived proton density fat fraction (MRI-PDFF) has the highest diagnostic accuracy and is used for trial enrolment and to evaluate therapeutic effects in early-phase clinical trials in nonalcoholic steatohepatitis (NASH). In patients with NAFLD without advanced fibrosis, high levels of liver fat are associated with rapid disease progression. Furthermore, changes on MRI-PDFF (≥30% decline relative to baseline) are associated with NAFLD activity score improvement and fibrosis regression. However, an inverse association exists between liver fat and complications of cirrhosis. Liver fat decreases as liver fibrosis progresses towards cirrhosis, and the clinical importance of quantitative measurements of liver fat differs by NAFLD status. As such, patients with NAFLD should be stratified by fibrosis severity to investigate the utility of quantitative measurements of liver fat for assessing NAFLD progression and prognosis.

Significant effects of Ganoderma lucidum polysaccharide on lipid metabolism in diabetes may be associated with the activation of the FAM3C-HSF1-CAM signaling pathway.

Diabetes is a threat to patient health worldwide. Type 2 diabetes (T2DM), one of the two main types of diabetes, is a long-term metabolic disease caused by heredity and environmental factors. It has been reported that Ganoderma lucidum polysaccharide (GLP) significantly decreased the concentration of blood glucose, promoted insulin secretion, improved glucose tolerance and regulated the concentration of blood lipids. In the present study, a T2DM model was established in db/db mice, following which T2DM mice were treated with GLP (100 and 400 mg/kg) for 8 weeks, with MET used as the positive control. The glycosylated hemoglobin (HbAlc) and fasting blood glucose (FBG) levels, and diabetes-associated clinical chemistry indexes were detected in the blood and serum of each mouse. Hematoxylin and eosin, and oil red O staining were performed on the livers of each mouse to evaluate the level of liver fat. The expression levels of family with sequence similarity 3 (FAM3C), heat shock factor 1 (HSF1), calmodulin (CaM), AKT and phosphorylated (p)-AKT were detected in the hepatocytes of T2DM mice using reverse transcription-quantitative PCR and western blotting. The results demonstrated that the unbalanced levels of HbAlc, FBG and diabetes-related index in T2DM mice were significantly improved by treatment with GLP. Lipid droplets in the hepatocytes of mice shrank in the GLP groups compared with the model control group. The expression levels of FAM3C, HSF1, CaM and p-AKT/AKT in the hepatocytes of T2DM mice were significantly increased following treatment with GLP. In conclusion, GLP exerted significant effects on lipid metabolism in diabetes, which may be associated with the activation of the FAM3C-HSF1-CaM signaling pathway.

Untargeted metabolomics reveals plasma metabolites predictive of ectopic fat in pancreas and liver as assessed by magnetic resonance imaging: the TOFI_Asia study

BackgroundExcess visceral obesity and ectopic organ fat is associated with increased risk of cardiometabolic disease. However, circulating markers for early detection of ectopic fat, particularly pancreas and liver, are lacking.MethodsLipid storage in pancreas, liver, abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 68 healthy or pre-diabetic Caucasian and Chinese women enroled in the TOFI_Asia study was assessed by magnetic resonance imaging/spectroscopy (MRI/S). Plasma metabolites were measured with untargeted liquid chromatography–mass spectroscopy (LC–MS). Multivariate partial least squares (PLS) regression identified metabolites predictive of VAT/SAT and ectopic fat; univariate linear regression adjusting for potential covariates identified individual metabolites associated with VAT/SAT and ectopic fat; linear regression adjusted for ethnicity identified clinical and anthropometric correlates for each fat depot.ResultsPLS identified 56, 64 and 31 metabolites which jointly predicted pancreatic fat (R2Y = 0.81, Q2 = 0.69), liver fat (RY2 = 0.8, Q2 = 0.66) and VAT/SAT ((R2Y = 0.7, Q2 = 0.62)) respectively. Among the PLS-identified metabolites, none of them remained significantly associated with pancreatic fat after adjusting for all covariates. Dihydrosphingomyelin (dhSM(d36:0)), 3 phosphatidylethanolamines, 5 diacylglycerols (DG) and 40 triacylglycerols (TG) were associated with liver fat independent of covariates. Three DGs and 12 TGs were associated with VAT/SAT independent of covariates. Notably, comparison with clinical correlates showed better predictivity of ectopic fat by these PLS-identified plasma metabolite markers.ConclusionsUntargeted metabolomics identified candidate markers of visceral and ectopic fat that improved fat level prediction over clinical markers. Several plasma metabolites were associated with level of liver fat and VAT/SAT ratio independent of age, total and visceral adiposity, whereas pancreatic fat deposition was only associated with increased sulfolithocholic acid independent of adiposity-related parameters, but not age.

Meta-analysis of the effect of sodium-glucose cotransporter2 inhibitors on hepatic fibrosis in patients with type2 diabetes mellitus complicated with non-alcoholic fatty liver disease.

This study aimed to analyze the effects of sodium-glucose cotransporter2 (SGLT2) inhibitors on the indexes of liver fibrosis in patients with type2 diabetes mellitus complicated with non-alcoholic fatty liver disease, and also to observe the effects on liver enzymes and liver fat. This meta-analysis was performed using RevMan 5.3 statistical software. SGLT2 inhibitors could significantly reduce the level of hepatic fibrosis index: fibrosis-4 (mean difference [MD] 0.25, 95% CI -0.39 to -0.11, p=0.0007); serum typeⅣ collagen 7s (MD 0.32, 95% CI -0.59 to -0.04, p=0.02); and ferritin (MD 26.7, 95% CI 50.64, 2.76, p=0.03). SGLT2 inhibitors could significantly reduce the level of liver enzymes: alanine aminotransferase (MD 3.49, 95% CI -5.1 to 1.58, p<0.0001); aspartate aminotransferase (MD 3.64, 95% CI -5.10 to -2.18, p<0.00001); and glutamate aminotransferase (MD 7.13, 95% CI -12.95 to -1.32, p=0.02). SGLT2 inhibitors could significantly reduce the level of liver fat: liver-to-spleen attenuation ratio (MD 0.16, 95% CI 0.10-0.22, p<0.00001); magnetic resonance imaging proton density fat fraction (MD 1.97, 95% CI -3.49 to -0.45, p=0.01); liver controlled attenuation parameter (MD 0.29, 95% CI -26.95 to -13.64, p<0.00001); liver fat score (MD 0.55, 95% CI 1.04 to -0.05, p=0.03); and liver fat index (MD 11.21, 95% CI -16.53 to -5.89, p<0.0001). SGLT2 inhibitors could improve liver fibrosis, liver enzymes, liver fat, and metabolic indexes in patients with type2 diabetes mellitus complicated with non-alcoholic fatty liver disease.

Effects of Flaxseed and Multi-Carbohydrase Enzymes on the Cecal Microbiota and Liver Inflammation of Laying Hens.

Simple SummaryWheat and flaxseed are used worldwide to produce omega-3 (ω-3) enriched poultry meat and eggs, however, wheat and flaxseed contain some anti-nutritional factors (ANFs). In addition, the supplementation of feed additive including enzymes usually alleviate the deleterious influence of ANFs. Therefore, we conducted the current study of laying hens fed with two diets (corn/flaxseed and wheat/flaxseed, supplemented with three enzymes), for a period of 10 weeks. Here, we found a clear increase in the fat weight of birds fed with corn diet as compared with wheat diet. Moreover, a high level of secretory IL-1β, IL-6, and IL-10 and comparatively higher inflammatory changes in the liver tissue were found in birds fed with corn diet as compared with wheat diet. The gut microbial composition of hens fed with corn diet was clearly different than that of birds fed a wheat diet. In conclusion, our findings suggest that inflammatory changes in laying birds were mediated by a corn diet with flaxseed and enzymes instead of a wheat diet. Additionally, in the wheat-fed group, enzyme-b and -c showed more encouraging results as compared to enzyme-a indicating that wheat diet might be a preferable diet for commercial layers poultry farms.Background: The use of wheat and flaxseed to produce omega-3 (ω-3) enriched poultry meat and eggs is very popular in the world. However, wheat and flaxseed contain some anti-nutritional factors (ANFs), and enzymes are usually used to alleviate the deleterious influence of ANFs. Method: A 2 × 3 two factors design was used in the experiment. A total of 540 twenty-week-old Nongda-3 laying hens were randomly allocated to six dietary treatments, two diets (corn/flaxseed and wheat/flaxseed), and three enzymes (enzyme-a contains neutral protease 10,000, xylanase 35,000, β-mannanase 1500, β-glucanase 2000, cellulose 500, amylase 100, and pectinase 10,000 (U g−1); enzyme-b contains alkaline protease 40,000 and neutral protease 10,000 (U g−1); enzyme-c contains alkaline protease 40,000, neutral protease 10,000, and cellulase 4000 (U g−1). Results: There was an interaction between dietary treatment and supplemental enzymes for liver weight and liver inflammatory cytokines of broilers. A significant increase was observed in the fat weight of birds fed a corn diet as compared with a wheat diet. A corn diet and wheat diet with the addition of enzyme-a (p < 0.001) showed the highest level of liver fat followed by enzyme-c (p < 0.01) and enzyme-b. Moreover, a high level of secretory IL-1β, IL-6, and IL-10 and comparatively higher inflammatory changes in the liver tissue were found in birds fed a corn diet as compared with a wheat diet, and enzyme-b showed more beneficial effects as compared with enzyme-a and -c. The gut microbial composition of hens fed a corn diet was significantly different than that of birds fed a wheat diet. Bacteroides were significantly (p < 0.05) abundant in the corn-fed birds as compared with wheat-fed birds. However, Firmicutes were less abundant in the wheat-fed birds than the corn-fed birds (16.99 vs. 31.80%, respectively). The microbial community at the genus level differed significantly in the dietary groups and we observed that Bacteroides are the predominant cecal microbiota. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of co-factors, carbohydrates, vitamins, protein, and energy were expressed at slightly higher levels in the microbiota of the wheat-fed birds, whereas, metabolic pathways for nucleotides, lipids, and glycine were expressed at higher levels in the wheat-fed birds. Furthermore, expression of the growth and cellular processes pathway and endocrine system pathway levels were predicted to be higher for the wheat-fed group as compared with the corn-fed group. Conclusions: In conclusion, our findings suggest that inflammatory changes in laying birds were mediated by a corn diet with flaxseed and enzymes instead of a wheat diet. Additionally, in the wheat-fed group, enzyme-b and -c showed more encouraging results as compared to enzyme-a.