Lower Liver Fat Research Articles

Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.

Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR; defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans. Cross-sectional study in men and women across a range of adiposity. Medication-free participants (n=177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast. Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups. Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF and these pathways should be considered for therapeutic targeting.

A flavonoid-rich diet is associated with lower risk and improved imaging biomarkers of nonalcoholic fatty liver disease: a prospective cohort study

BackgroundMechanistic studies and short-term randomized trials suggest higher intakes of dietary flavonoids may protect against nonalcoholic fatty liver disease (NAFLD). ObjectivesWe aimed to perform the first population-based study with long-term follow-up on flavonoid consumption, incident NAFLD, and validated NAFLD biomarkers. MethodsIn a prospective study, we assessed the associations between flavonoid intake based on ≥2 24-h dietary assessments and NAFLD risk among 121,064 adults aged 40–69 y by multivariable Cox regression analyses. We further assessed the associations between flavonoid intake and magnetic resonance imaging-derived liver fat (a subset of n = 11,435) and liver-corrected T1 values (cT1; a subset of n = 9570), a marker of steatosis, more sensitive to inflammatory pathology. ResultsOver 10 y of follow-up, 1081 cases of NAFLD were identified. Participants in the highest quartile (Q4) of the flavodiet score reflecting the consumption of foods high in flavonoids, had a 19% lower risk of NAFLD compared to the lowest quartile (Q1) [hazard ratio (HR) (95% confidence interval (CI): 0.81 (0.67, 0.97), P-trend = 0.02)]. Moreover, participants in the Q4 of the flavodiet score had lower liver fat and cT1 values than those in Q1 (liver fat: relative difference Q1 compared with Q4: –5.28%, P-trend = <0.001; cT1: relative difference Q1 compared with Q4: –1.73%, P-trend = <0.001). When compared to low intakes, high intakes of apples and tea were associated with lower NAFLD risk [apples: HR (95% CI): 0.78 (0.67, 0.92), P-trend = <0.01; tea: HR (95% CI): 0.86 (0.72, 1.02), P-trend = 0.03)]. Additionally, when compared to low intakes, high apple, tea, and dark chocolate intakes were significantly associated with lower liver fat values, whereas high tea and red pepper intakes were significantly associated with lower cT1 values. ConclusionsThe consumption of flavonoid-rich foods was associated with a reduced risk of NAFLD among middle-aged adults.

Liver transplant recipients have worse metabolic body phenotype compared with matched non-transplant controls.

Quantification of body compartments, particularly the interaction between adipose tissue and skeletal muscle, is emerging as novel a biomarker of metabolic health. The present study evaluated the impact of liver transplant (LT) on body compartments. Totally 66 adult LT recipients were enrolled in whom body compartments including visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), muscle fat infiltration (MFI), fat-free muscle volume (FFMV), and liver fat (LF) were quantified via whole body magnetic resonance imaging (MRI). To provide non-LT comparison, each LT recipient was matched to at least 150 non-LT controls for same sex, age, and body mass index (BMI) from the UK Biobank registry. LT recipients (vs matched non-LT controls) had significantly higher subcutaneous (13.82 ± 5.47 vs 12.10 ± 5.10 L, P < 0.001) and visceral fat (7.59 ± 3.75 vs 6.72 ± 3.06 L, P = 0.003) and lower LF (5.88 ± 7.14 vs 8.75 ± 6.50%, P < 0.001) and muscle volume (11.69 ± 2.95 vs 12.12 ± 2.90 L, P = 0.027). In subgroup analysis, patients transplanted for metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis (vs non-MASH cirrhosis) had higher ASAT, VAT, and MFI. A trend toward higher LF content was noted; however, this did not reach statistical significance (6.90 ± 7.35 vs 4.04 ± 6.23%, P = 0.189). Finally, compared with matched non-LT controls, patients transplanted for MASH cirrhosis had higher ASAT and VAT; however, FFMV and MFI were similar. Using non-LT controls, the current study established the higher-than-expected adiposity burden among LT recipients, which is even higher among patients transplanted for MASH cirrhosis. These findings provide data needed to design future studies developing radiomics-based risk-stratification strategies in LT recipients.

Liver fat accumulation is associated with increased insulin secretion independent of total, visceral, and pancreatic fat.

Studies in heterogenous groups of people with respect to sex, body mass index (BMI), and glycemic status (normoglycemia, impaired glucose tolerance, diabetes), indicate no relationship between liver fat accumulation and pancreatic insulin secretion. To better understand the association of liver fat with insulin secretion. Cross-sectional analysis of 61 men with abdominal obesity who had high liver fat (HLF, ≥5.6% by magnetic resonance spectroscopy, n=28) or low liver fat (LLF, n=33), but were balanced on BMI, total body fat, visceral adipose tissue (VAT), and pancreatic fat. A frequently sampled 5-hour oral glucose tolerance test with 11 samples, in conjunction with mathematical modeling, was used to compute indices of insulin sensitivity and insulin secretion (oral minimal model). Compared to subjects with LLF, those with HLF had significantly greater fasting glucose, insulin, C-peptide, and triglyceride; lower high-density lipoprotein-cholesterol; but similar glycated hemoglobin. Areas under the 5-hour curve for glucose, insulin, and C-peptide were greater in the HLF group than the LLF group (by ∼10%, ∼38%, and ∼28%, respectively); fasting and total postprandial insulin secretion rates were ∼37% and ∼50% greater, respectively (all P<0.05); whereas the insulinogenic index was not different. HLF subjects had lower whole-body and hepatic insulin sensitivity, disposition index, and total insulin clearance than LLF subjects (all P<0.05). Accumulation of liver fat is associated with increased insulin secretion independently of total adiposity, abdominal fat distribution, and pancreatic fat. Thereby, hyperinsulinemia in fatty liver disease is partly because of insulin hypersecretion and partly because of impaired insulin clearance.

Liver fibrosis and liver stiffness in patients with obesity and type 1 diabetes.

To compare hepatic stiffness and fat fraction in patients with obesity and type 1 diabetes (T1D) with type 2 diabetes (T2D) with a similar body mass index (BMI). In this prospective cross-sectional study, 90 participants with T1D (BMI 30.5 ± 4.5 kg/m2; diabetes duration 20.5 ± 9.8 years; HbA1c 8.2% ± 1.4%) and 69 with T2D (BMI: 30.8 ± 4.6 kg/m2; diabetes duration: 11.7 ± 7.8 years; HbA1c: 7.3% ± 1.4%) were included. Liver fat fraction and stiffness were examined by magnetic resonance imaging and elastography, respectively. Logistic regressions were used to evaluate associations with biomedical variables. The mean liver stiffness score in patients with obesity and T1D was 2.2 ± 0.5 kPa, while in T2D it was 2.6 ± 0.8 kPa (P < .001). The liver fat fraction in patients with obesity and T1D was 3.7% ± 6.3%, and in T2D it was 10.6% ± 7.9% (P < .001). Metabolic dysfunction-associated steatotic liver disease (MASLD) was present in 13.3% of patients with T1D and in 69.6% of patients with T2D, whereas fibrosis was suggested in 7.8% of patients with T1D and in 27.5% of patients with T2D. Liver stiffness was four times higher in patients with T2D compared with those with T1D (odds ratio = 5.4, 95% confidence interval: 2.1-13.6, P < .001). Aspartate transaminase (AST), alanine transaminase, gamma-glutamyl transferase (GGT), triglycerides and the android-to-gynoid ratio were associated with elevated fat fraction in both cohorts. AST and GGT were associated with elevated liver stiffness in both cohorts. Patients with obesity and T1D had lower liver fat and liver stiffness compared with those patients with T2D, despite similar levels of BMI, a longer duration of diabetes and worse glycaemic control.

Adipose Tissue Insulin Resistance Correlates with Disease Severity in Pediatric Metabolic Dysfunction-Associated Steatotic Liver Disease: A Prospective Cohort Study

ObjectivesTo assess the role of adipose tissue insulin resistance (Adipo-IR) in the pathogenesis of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) and to determine Adipo-IR evolution during a lifestyle intervention program. Study designIn this prospective, cohort study, children and adolescents with severe obesity were recruited between July 2020 and December 2022 at an inpatient pediatric rehabilitation center. Treatment consisted of dietary intervention and physical activity. Liver steatosis and fibrosis were evaluated using ultrasound and transient elastography with controlled attenuation parameter and liver stiffness measurement. Every 4 to 6 months, anthropometric measurements, serum biochemical analysis, ultrasound and elastography were repeated. Adipo-IR was estimated by the product of the fasting serum insulin times the fasting free fatty acid concentration and hepatic IR by the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. Results56% of 200 patients with obesity had evidence of steatosis on ultrasound and 26% were diagnosed with fibrosis (≥F2). Adipo-IR increased progressively from lean controls to patients with obesity to patients with MASLD and MASLD with fibrosis. Adipo-IR was already elevated in patients with only mild steatosis (p = 0.0403). Patients with more insulin-sensitive adipose tissue exhibited lower liver fat content (p < 0.05) and serum alanine transaminase levels (p = 0.001). Adipo-IR correlated positively with visceral adipose tissue weight, waist circumference, and the visceral adipose tissue/gynoid adipose tissue ratio (p < 0.001), but not with total body fat percentage (p = 0.263). After 4 to 6 months of lifestyle management, both MASLD and Adipo-IR improved. ConclusionsOur data suggest that Adipo-IR is associated with the presence of pediatric MASLD, particularly steatosis.

Ablation of IFNγ in myeloid cells suppresses liver inflammation and fibrogenesis in mice with hepatic small heterodimer partner (SHP) deletion

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication of obesity and, in severe cases, progresses to metabolic dysfunction-associated steatohepatitis (MASH). Small heterodimer partner (SHP) is an orphan member of the nuclear receptor superfamily and regulates metabolism and inflammation in the liver via a variety of pathways. In this study, we investigate the molecular foundation of MASH progression in mice with hepatic SHP deletion and explore possible therapeutic means to reduce MASH. MethodsHepatic SHP knockout mice (SHPΔhep) and their wild-type littermates (SHPfl/fl) of both sexes were fed a fructose diet for 14 weeks and subjected to an oral glucose tolerance test. Then, plasma lipids were determined, and liver lipid metabolism and inflammation pathways were analyzed with immunoblotting, RNAseq, and qPCR assays. To explore possible therapeutic intersections of SHP and inflammatory pathways, SHPΔhep mice were reconstituted with bone marrow lacking interferon γ (IFNγ−/−) to suppress inflammation. ResultsHepatic deletion of SHP in mice fed a fructose diet decreased liver fat and increased proteins for fatty acid oxidation and liver lipid uptake, including UCP1, CPT1α, ACDAM, and SRBI. Despite lower liver fat, hepatic SHP deletion increased liver inflammatory F4/80+ cells and mRNA levels of inflammatory cytokines (IL-12, IL-6, Ccl2, and IFNγ) in both sexes and elevated endoplasmic reticulum stress markers of Cox2 and CHOP in female mice. Liver bulk RNAseq data showed upregulation of genes whose protein products regulate lipid transport, fatty acid oxidation, and inflammation in SHPΔhep mice. The increased inflammation and fibrosis in SHPΔhep mice were corrected with bone marrow-derived IFNγ−/− myeloid cell transplantation. ConclusionHepatic deletion of SHP improves fatty liver but worsens hepatic inflammation possibly by driving excess fatty acid oxidation, which is corrected by deletion of IFNγ specifically in myeloid cells. This suggests that hepatic SHP limits fatty acid oxidation during fructose diet feeding but, in doing so, prevents pro-MASH pathways. The IFNγ-mediated inflammation in myeloid cells appears to be a potential therapeutic target to suppress MASH.

Effect of repeated prolonged exercise on liver fat content and visceral adipose tissue in well-trained older men.

Liver fat (LF) and visceral adipose tissue (VAT) content decreases with training, however, this has mainly been investigated in sedentary obese or healthy participants. The aim of this study was to investigate the effects of repeated prolonged exercise on LF and VAT content in well-trained older men and to compare baseline LF and VAT content to recreationally active older men. A group of five well-trained older men were tested before and after cycling a total distance of 2558 km in 16 consecutive days. VAT content and body composition was measured using DXA before a bicycle ergometer test was performed to determine maximal fat oxidation (MFO), maximal oxygen consumption ( ), and the relative intensity at which MFO occurred (Fatmax). LFcontent was measured on a separate day using MRI. For comparison of baseline values, a control group of eight healthy age- and BMI-matched recreationally active men were recruited. The well-trained older men had lower VAT (p = 0.02), and a tendency toward lower LF content (p = 0.06) compared with the control group. The intervention resulted in decreased LF content (p = 0.02), but VAT, fat mass, and lean mass remained unchanged. , MFO, and Fatmax were not affected by the intervention. The study found that repeated prolonged exercise reduced LF content, but VAT and remained unchanged. Aerobic capacity was aligned with lower LF and VAT in older active men.

Genetic Evidence for Distinct Biological Mechanisms That Link Adiposity to Type 2 Diabetes: Toward Precision Medicine.

We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We employed MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites and Magnetic Resonance Imaging-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size, enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat.

Spleen volume is independently associated with non-alcoholic fatty liver disease, liver volume and liver fibrosis

Non-alcoholic fatty liver disease (NAFLD) can lead to irreversible liver damage manifesting in systemic effects (e.g., elevated portal vein pressure and splenomegaly) with increased risk of deadly outcomes. However, the association of spleen volume with NAFLD and related type 2-diabetes (T2D) is not fully understood. The UK Biobank contains comprehensive health-data of 500,000 participants, including clinical data and MR images of >40,000 individuals. The present study estimated the spleen volume of 37,066 participants through automated deep learning-based image segmentation of neck-to-knee MR images. The aim was to investigate the associations of spleen volume with NAFLD, T2D and liver fibrosis, while adjusting for natural confounders. The recent redefinition and new designation of NAFLD to metabolic dysfunction-associated steatotic liver disease (MASLD), promoted by major organisations of studies on liver disease, was not employed as introduced after the conduct of this study. The results showed that spleen volume decreased with age, correlated positively with body size and was smaller in females compared to males. Larger spleens were observed in subjects with NAFLD and T2D compared to controls. Spleen volume was also positively and independently associated with liver fat fraction, liver volume and the fibrosis-4 score, with notable volumetric increases already at low liver fat fractions and volumes, but not independently associated with T2D. These results suggest a link between spleen volume and NAFLD already at an early stage of the disease, potentially due to initial rise in portal vein pressure.

The cross-sectional area of erector spinae muscle and the liver-to-spleen ratio are associated with frailty in older patients with diabetes: a cross-sectional study

BackgroundOlder patients with diabetes mellitus are more susceptible to frailty. Although some imaging markers of appendicular skeletal muscle mass obtained using dual-energy X-ray absorptiometry or computed tomography (CT) imaging can reflect frailty status, the association between imaging indices obtained by abdominal CT scans and frailty in older inpatients has not been reported.MethodsA total of 151 older inpatients with diabetes mellitus (median age, 79 years; men, 42%) who underwent abdominal CT scans close to the admission date were studied to examine the associations between abdominal CT indices and frailty. Two frailty definitions were used: the modified Cardiovascular Health Study (mCHS) criteria and Kihon Checklist (KCL) criteria. Using the imaging analysis software SYNAPSE VINCENT®, we compared the cross-sectional areas (CSA) of four truncal muscles (erector spinae, iliopsoas, rectus abdominis, and abdominal oblique muscles) and the liver-to-spleen ratio (L/S), the ratio of the CT values of the liver and spleen between frail and non-frail patients. The muscle areas that showed the strongest associations with frailty were also investigated in relation to grip strength and walking speed. Finally, multivariate binominal logistic regression analyses were performed to assess the independent associations of CSA of muscle and L/S with the prevalence of frailty.ResultsThe prevalence of frailty defined by the mCHS and KCL criteria was 55% and 52%, respectively. The CSA of the erector spinae muscle was most significantly associated with frailty, and was significantly smaller in both sexes of mCHS-defined frail patients and in men with KCL-defined frailty. The CSA of erector spinae muscle was also positively correlated with grip strength and walking speed. In contrast, the L/S was higher in men with KCL-defined frailty. Multivariate logistic regression analyses revealed that the CSA of the erector spinae muscle was independently associated with mCHS-defined frailty in women, and the L/S was associated with KCL-defined frailty in men.ConclusionsThe CSA of erector spinae muscle and low liver fat content could be indices of frailty in older patients with diabetes.

Low liver fat in non-alcoholic steatohepatitis-related significant fibrosis and cirrhosis is associated with hepatocellular carcinoma, decompensation and mortality.

Progression to cirrhosis in non-alcoholic steatohepatitis (NASH) is associated with a decrease in liver fat. However, the prognostic significance of liver fat content in NASH-related significant fibrosis and cirrhosis is unclear. To investigate the risk of decompensation, hepatocellular carcinoma (HCC) and mortality stratified by liver fat content in NASH-related significant fibrosis and cirrhosis. In this meta-analysis of individual participant data, 456 patients with both magnetic resonance elastography (MRE) and MRI-derived protein density fat fraction (MRI-PDFF) were enrolled, and 296 patients with longitudinal follow-up were analysed. MRE combined with fibrosis-4 (MEFIB-index), and MRI-PDFF were used to measure liver fibrosis and fat, respectively. MEFIB-negative, MEFIB-positive+ MRI-PDFF ≥5% and MEFIB-positive+ MRI-PDFF <5% were defined as no significant liver fibrosis, NASH with significant fibrosis and higher liver fat content, and NASH with significant fibrosis and low liver fat content groups, respectively. The primary outcome was hepatic decompensation, HCC and death. The rates of decompensation, HCC and mortality were highest in the NASH with significant fibrosis and low liver fat group (33%, 17% and 17%, respectively), followed by the NASH with significant fibrosis and higher liver fat group (18%, 13% and 13% respectively), and lowest in the no significant fibrosis (MEFIB-negative) group (0%, 1% and 2% respectively). In multivariable-adjusted analysis, low liver fat content was strongly associated (HR = 42.2 [95% CI: 7.5-235.5, p < 0.0001]) with HCC, decompensation and death. Sensitivity analyses for patients with cirrhosis (MRE ≥5 kPa) determined consistent findings. Low liver fat content in patients with burnt-out NASH-related significant fibrosis and cirrhosis is associated with an increase in hepatic decompensation, HCC and mortality.

Liver Fat and Its Association with Time to Biochemical Failure (TTBCF) after Definitive Treatment to the Prostate

Elevated body mass index (BMI) is associated with an increased risk of biochemical failure (BCF); however, BMI may not best capture underlying health. We examined a different metric, liver fat, which may better approximate the body's metabolic state, to see its association with time to biochemical failure (TTBCF) in patients treated definitively for prostate cancer. Of 210 patients who received a PSMA PET/CT at our institution, we identified 60 men treated with either prostatectomy or definitive radiation without androgen deprivation therapy who developed BCF. BCF was defined as PSA ≥ 0.2 ng/mL if treated with prostatectomy or PSA nadir + 2 ng/mL for those treated with definitive radiation. All prostatectomy patients had a post-op PSA < 0.1. Liver fat was evaluated via the non-contrast portion of respective PSMA PET/CT scans. Average Hounsfield Units (HU) of the liver were used to split individuals into high (≤ 56.1) and low (> 56.1) liver fat. A threshold of 56.1 HU was chosen as it corresponds to 5.56% liver fat, or the 95th percentile of non-obese, non-diabetic controls. Liver fat was quantified by converting HU to proton density fat fraction (PDFF) using the formula: PDFF = -0.582*HU + 38.214. Median TTBCF was estimated using Kaplan Meier methods, and Cox Proportional Hazards Regression was used for covariate adjustment. Forty-four patients were classified as having high liver fat (HLF) and 16 as having low liver fat (LLF). Patients with HLF were more likely to have a higher BMI, have high risk disease, undergo surgery, and have shorter TTBCF (Table). When adjusted for NCCN risk category and treatment type, HLF was associated with twice the risk of BCF per unit time (aHR = 2.02, 95% CI [1.09 - 3.73], p = 0.03). With additional adjustment for BMI (continuous), HLF was no longer an independent predictor of TTBCF (aHR = 1.75, 95% CI [0.94 - 3.25], p = 0.08). In this small study of patients who had biochemical failure after completing definitive treatment to the prostate, those with liver fat ≥ 5.56% were more likely to fail sooner, adjusting for risk category and treatment type. This project suggests that a man with elevated liver fat, on average, experiences a shorter interval free from prostate cancer.

Methods and Reproducibility of Liver Fat Measurement Using 3-Dimensional Liver Segmentation From Noncontrast Computed Tomography in EVAPORATE Cohort.

Nonalcoholic fatty liver disease not only shares multiple risk factors with cardiovascular disease but also independently predicts its increased risk and related outcomes. Here, we evaluate reproducibility of 3-dimensional (3D) liver volume segmentation method to identify fatty liver on noncontrast cardiac computed tomography (CT) and compare measures with previously validated 2-dimensional (2D) segmentation CT criteria for the measurement of liver fat. The study included 68 participants enrolled in the EVAPORATE trial and underwent serial noncontrast cardiac CT. Liver attenuation < 40 Hounsfield units (HU) was used for diagnosing fatty liver, as done in the MESA study. Two-dimensional and 3D segmentation of the liver were performed by Philips software. Bland-Altman plot analysis was used to assess reproducibility. Interreader reproducibility of 3D liver mean HU measurements was 96% in a sample of 111 scans. Reproducibility of 2D and 3D liver mean HU measurements was 93% in a sample of 111 scans. Reproducibility of change in 2D and 3D liver mean HU was 94% in 68 scans. Kappa, a measure of agreement in which the 2D and 3D measures both identified fatty liver, was excellent at 96.4% in 111 scans. Fatty liver can be reliably diagnosed and measured serially in a stable and reproducible way by 3D liver segmentation of noncontrast cardiac CT scans. Future studies need to explore the sensitivity and stability of measures for low liver fat content by 3D segmentation, over the current 2D methodology. This measure can serve as an imaging biomarker to understand mechanistic correlations between atherosclerosis, fatty liver, and cardiovascular disease risk.

Clinical utility of liver fat quantification for determining cardiovascular disease risk among patients with type 2 diabetes.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are independent risk factors for cardiovascular disease (CVD). To examine the clinical utility of liver fat quantification for determining CVD risk among a well-phenotyped cohort of patients with T2DM. This was a cross-sectional analysis of a prospective cohort of adults aged ≥50 with T2DM. Liver fat was quantified with magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF), an advanced imaging-based biomarker. Patients were stratified into a higher liver fat group (MRI-PDFF ≥ 14.6%), and a lower liver fat group (MRI-PDFF < 14.6%). The co-primary outcomes were CVD risk determined by Framingham and Atherosclerotic Cardiovascular Disease (ASCVD) risk scores. High CVD risk was defined by risk scores ≥20%. Of the 391 adults (66% female) in this study, the mean (±SD) age was 64 (±8) years and BMI 30.8 (±5.2) kg/m2 , respectively. In multivariable analysis, adjusted for age, gender, race, and BMI, patients in the higher liver fat group had higher CVD risk [OR = 4.04 (95% CI: 2.07-7.88, p < 0.0001)] and ASCVD risk score [OR = 2.85 (95% CI: 1.19-6.83, p = 0.018)], respectively. Higher liver fat content increases CVD risk independently of age, gender, ethnicity and BMI. These findings raise the question whether liver fat quantification should be incorporated into risk calculators to further stratify those with higher CVD risk.

96-OR: Liver Fibrosis Scores in Novel Subclusters of Patients at Risk for Type 2 Diabetes

Metabolic diseases such as type 2 diabetes (T2D) are linked to the development of fatty liver, steatohepatitis and liver fibrosis. We have previously described novel clusters of patients at risk for T2D. Three clusters (3, 5 and 6) either had a high risk to progress to T2D or to develop cardiorenal complications. While high-risk clusters differ in liver fat content, it remains unknown if they also harbor a different risk for hepatic fibrosis. Thus, we determined clinically applicable scores of liver fibrosis in 1115 subjects at risk for T2D from the TUEF/TULIP study, which were categorized into high-risk clusters (n=602). Liver fat content was determined by 1H-magnetic resonance spectroscopy. The AST-to-platelet-ratio index (APRI), fibrosis-4 score (FIB-4) and NAFLD fibrosis score (NFS) were used to determine fibrosis risk. ANCOVA model analysis adjusted for liver fat content was performed. Of the high-risk clusters (3: n= 83, 5: n= 203, 6: n= 316), cluster 6 had the highest BMI 44.1±9.7 kg/m² (vs. cluster 3: 29.7±3.1 kg/m², p&amp;lt;0.001 and cluster 5: 42.8.0±8.7, p=0.32) and cluster 5 had the highest liver fat content (13.4±8.8% vs. cluster 3: 8.0±6.5, p&amp;lt;0.001 and cluster 6: 9.0±6.7, p&amp;lt;0.001). All fibrosis scores correlated with liver fat content (e.g. FIB-4: r= 0.45, p&amp;lt; 0.0001). Although FIB-4, APRI and NFS were generally low, they were highest in cluster 5, but despite highest liver fat content, they did not differ from cluster 3 and 6 (e.g. FIB-4: cluster 5: 0.19±0.45 vs. cluster 3: 0.14±0.01, p=0.59 and cluster 6: 0.12±0.15, p=0.39). Interestingly, cluster 3 with the lowest liver fat content exhibited higher FIB-4 compared to cluster 6 (p=0.02). According to clinically applicable scores, the most insulin resistant cluster 5 has the highest FIB-4 score. The insulin deficient cluster 3 has a relatively high FIB-4 score despite relatively low liver fat content and BMI. Further studies are needed to investigate the clinical relevance of these findings. Disclosure V.Minelli faiao: None. A.Peter: None. A.L.Birkenfeld: None. N.Stefan: Advisory Panel; Pfizer Inc., Research Support; Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Jumpertz von schwartzenberg: Other Relationship; Sanofi, Amgen Inc., Lilly, Novo Nordisk. A.Sandforth: None. S.Katzenstein: None. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. L.Fritsche: None. J.Machann: None. F.Schick: None. H.Häring: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi.

Alleviation of Hepatic Steatosis by Alpha-Defensin Is Associated with Enhanced Lipolysis.

Background and Objectives: The neutrophilic peptide, alpha-defensin, is considered an evolving risk factor intimately linked with lipid mobilization. It was previously linked to augmented liver fibrosis. Here, we assess a potential association between alpha-defensin and fatty liver. Materials and Methods: A cohort of transgenic C57BL/6JDef+/+ male mice that overexpress the human neutrophil-derived alpha-defensin in their polymorphonuclear neutrophils (PMNs) were assessed for liver steatosis and fibrosis development. Wild type (C57BL/6JDef.Wt) and transgenic (C57BL/6JDef+/+) mice were maintained on a standard rodent chow diet for 8.5 months. At the termination of the experiment, systemic metabolic indices and hepatic immunological cell profiling were assessed. Results: The Def+/+ transgenic mice exhibited lower body and liver weights, lower serum fasting glucose and cholesterol, and significantly lower liver fat content. These results were associated with impaired liver lymphocytes count and function (lower CD8, NK cells, and killing marker CD107a). The metabolic cage demonstrated dominant fat utilization with a comparable food intake in the Def+/+ mice. Conclusions: Chronic physiological expression of alpha-defensin induces favorable blood metabolic profile, increased systemic lipolysis, and decreased hepatic fat accumulation. Further studies are needed to characterize the defensin net liver effect.

Abstract MP12: Dash Diet and Its Components is Associated With Visceral Fat Area and Hepatic Attenuation Among South Asian Adults in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study (2010-2013)

Introduction: South Asians (SA) are a growing population group in the US that remain understudied in research despite their high cardiometabolic risk. Compared to other ethnic groups, SA experience cardiometabolic disease onset at a younger age, and have higher abdominal, visceral and hepatic fat despite lower BMI. SA in the US have a unique dietary pattern characterized by a combination of traditional and western food items. Examining the dietary pattern of SA in relation to central adiposity may provide a tenable strategy for disease prevention and treatment. Hypothesis: We assessed the hypothesis that higher DASH diet score is associated with lower central adiposity, indicated by visceral fat area and hepatic attenuation measurements, among SA in the US. Methods: Using baseline data from 822 adults enrolled in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study, we computed a Dietary Approaches to Stop Hypertension (DASH) concordance score from the FFQ validated to measure diet of South Asians in North America. Using an established method, score concordance was based on 8 components including high intake of fruit, vegetables, nuts/legumes, low-fat dairy products, whole grains; and low intake of sodium, sugar-sweetened beverages, and red/processed meats. We examined the association between the DASH score and its components with CT imaging of visceral fat area and hepatic attenuation (higher score indicates lower liver fat). Results: The overall DASH score among participants ranged from 13-35 (mean ± SD, 24.6 ± 4.4). Hepatic attenuation was 5 HU higher among participants in the highest category DASH score compared to the lowest (aβ (SE): 5 (1), 95% CI: 2, 7) in the age-adjusted model. The relationship was not significant in the fully adjusted model. Visceral fat area was 13.6 cm 2 lower among participants in the highest category of DASH score compared to the lowest (aβ (SE): -3.6 (5.1), 95% CI: -23.5, -3.7) in the model adjusted for age, sex, percent of life in US, education, BMI, physical activity, smoking, alcohol, and energy intake. When examining individual components of DASH, participants with the highest intake of low-fat dairy had hepatic attenuation 3 HU higher than those with the lowest intake, and those with the lowest intake of red/processed meat had hepatic attenuation 2 HU higher in the fully adjusted model. Participants with the lowest red/processed meat intake had visceral fat area that was 11 cm 2 lower in the fully adjusted model. Conclusions: In conclusion, our results indicate that greater adherence to DASH and some of its individual components is associated with favorable abdominal fat areas among a sample of SA adults in the US. These findings support the relationship between diet and abdominal fat accretion. Forthcoming analyses will use the DASH score to further elucidate the diet-disease relationship among SA in the US.

Research progress on chemical constituents of Schisandra chinensis and its effect on nonalcoholic fatty liver disease

Schisandra chinensis, a traditional Chinese medicinal herb, is rich in chemical constituents, including lignans, triterpenes, polysaccharides, and volatile oils. Clinically, it is commonly used to treat cardiovascular, cerebrovascular, liver, gastrointestinal, and respiratory diseases. Modern pharmacological studies have shown that S. chinensis extract and monomers have multiple pharmacological activities in lowering liver fat, alleviating insulin resistance, and resisting oxidative stress, and have good application prospects in alleviating nonalcoholic fatty liver disease(NAFLD). Therefore, this study reviewed the research progress on chemical constituents of S. chinensis and its effect on NAFLD in recent years to provide references for the research on S. chinensis in the treatment of NAFLD.

The association of multidimensional sleep health with adiposity in heart failure with preserved ejection fraction

BackgroundThere are bi-directional relationships between sleep disturbances and obesity, both of which are prevalent in patients with heart failure with preserved ejection fraction (HFpEF). However, little is known about the sleep-obesity association in HFpEF. ObjectivesTo determine associations of multidimensional sleep health, night movement, sleep fragmentation, and sleep-disordered breathing (SDB) risk with overall and regional adiposity in HFpEF patients. MethodsMen and women with HFpEF (n = 49) were assessed via 14-day actigraphy, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale to derive multidimensional sleep health. SDB risk was assessed via Berlin Questionnaire. Body composition was measured using anthropometry; MRI quantification of epicardial, abdominal, liver, and thigh adipose tissue was performed in a subsample (n = 22). Spearman correlation (rs) and linear regression analyses (β coefficient) were used to estimate bivariate and age-adjusted associations. ResultsMultidimensional sleep health was inversely associated with BMI (rs = -0.50, p < .001; unadjusted: β = -4.00, 95%CI: -5.87, -2.13; age-adjusted: β = -2.48, 95%CI: -4.65, -0.30), thigh subcutaneous adipose tissue (rs = -0.50, p = .018; unadjusted: β = -36.95, 95%CI: -67.31, -6.59), and thigh intermuscular fat (age-adjusted: β = -0.24, 95%CI: -0.48, -0.01). Night movement and sleep fragmentation were associated with greater intermuscular thigh and lower liver fat. High SDB risk was associated with a higher visceral-to-subcutaneous ratio of abdominal adiposity and lower thigh adiposity. ConclusionsAdverse multidimensional sleep health is associated with higher adiposity measures in HFpEF patients. Further studies are needed to determine whether intervening on sleep could ameliorate excess adiposity or whether weight loss could improve sleep quality in HFpEF.