Baseline Liver Fat Research Articles

Dietary Effect on Peripheral and Cerebral Vascular Function in Adults with Non-Alcoholic Fatty Liver Disease

Objective: Non-alcoholic fatty liver disease (NAFLD) is a recognized independent risk factor for cardiovascular and cerebrovascular dysfunction. The present study evaluated the effect of dietary interventions on peripheral and cerebral vascular function in individuals with NAFLD. Methods: We studied 30 middle-aged adults (55±9 years) with NAFLD or with elevated NAFLD risk (with prediabetes symptoms). Liver fat content was assessed via 1H magnetic resonance spectroscopy. NAFLD was defined as liver fat proton density fat fraction (PDFF) exceeding 5%. Participants were randomly assigned to a low-carbohydrate diet (carbohydrate intake <30 g/d) or a low-calorie diet (30% calorie intake reduction). Arterial stiffness (via brachial-ankle pulse wave velocity-baPWV), carotid artery intima-media thickness (IMT), endothelium-dependent vasodilation (via flow-mediated dilation-FMD), cerebrovascular reactivity (CVR) in the middle cerebral artery (MCA), and blood concentrations of cardiovascular risk factors were measured before and after a two-week dietary intervention. Results: Participants with NAFLD represented 70% of the current cohort. Following the dietary interventions, participants had significant reductions in body weight (95%CI [-3.22, -1.41 kg]) and fat mass (95%CI [-1.64, -0.56 kg]), accompanied by decreased liver fat content (95%CI [-2.62, -0.79%]). These changes were only evident in the NAFLD group with no significant differences between the two dietary interventions. Systolic and diastolic blood pressure as well as pulse pressure significantly decreased in both NAFLD and non-NAFLD groups. Total cholesterol (95%CI [-22.2, -1.5 mg/dL]) and triglyceride (95%CI [-30.4, -0.9 mg/dL]) concentrations decreased in those with NAFLD assigned to the low-carbohydrate diet. baPWV decreased (95%CI [-78.6, -12.4 cm/s]) only in individuals with NAFLD assigned to the low-calorie diet. FMD significantly increased (95%CI [0.5, 5.1%]) only in individuals with NAFLD assigned to the low-carbohydrate diet. Lower baseline liver fat content was associated with greater improvement in FMD (r=-0.60, p=0.008) in the NAFLD group. Carotid IMT and cerebrovascular parameters (e.g., pulsatility index, CVR, MCA blood flow velocity) remained unchanged in any groups. Changes in vascular function were not associated with the corresponding changes in liver fat content. Conclusion: The two-week dietary intervention involving either a low-carbohydrate or low-calorie diet elicited significant reductions in liver fat content and improvements in peripheral arterial stiffness and endothelium-dependent vasodilation in adults with NAFLD. UT Aging Initiatives. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

72-LB: DD01, a Novel Once-Weekly Dual GLP-1/Glucagon Receptor Agonist, Improves Metabolic Health and Achieves Rapid, Clinically Significant Reductions in Hepatic Steatosis following Only Four Weeks of Treatment and without the Need for Significant Weight Loss in Overweight/Diabetic Subjects with NAFLD

DD01 is a dual GLP-1/glucagon receptor agonist acting through two independent pathways to provide rapid resolution of hepatic steatosis, improve glucose control, an reduce body weight in subjects with type 2 diabetes who are obese/overweight and have NAFLD. In a recently completed Phase 1 single and repeat dose safety and pharmacology study, DD01 was well tolerated and improved fasting and fed glucose while providing significant reductions in liver fat as measured by MRI-PDFF. Following only 4 weeks of once-weekly treatment, up to 100% of patients achieved ≥30% reduction in MRI-PDFF. In the high dose group, all subjects achieved at least a 40% reduction in liver fat with a mean reduction of 52% whereas the change from baseline liver fat in the placebo group was only 2.8%. Meaningful and rapid improvements in steatosis were observed at well-tolerated doses that did not cause significant weight loss, thus uncoupling the need for weight loss to precede or coincide with significant improvements in liver health. Disclosure D. To: Employee; Neuraly Inc. J. Shin: Employee; D&D Pharmatech. S. Karanth: None. Y. Lin: None. S. Sosnovtseva: None. A. C. Bell: None.

Associations of liver fat content with cardiometabolic phenotypes and outcomes in a multi-ethnic population: Results from the Dallas Heart Study.

To evaluate the associations between liver fat content and cardiometabolic parameters to explore potential threshold values that define metabolically healthy liver fat content, and to examine the association of liver fat content with cardiovascular events as well as its longitudinal progression. Participants in the Dallas Heart Study underwent clinical evaluation, including laboratory testing, and liver fat quantification by magnetic resonance spectroscopy (MRS) at baseline (N=2287) and at follow-up (N=343) after a mean of 7.3 years. Cardiovascular events were adjudicated (>12 years). The mean age at study entry was 44 years, 47% of participants were men, and 48% were African American. The following cardiometabolic biomarkers worsened across liver fat quintiles (P < 0.0001): body mass index (BMI); waist circumference; prevalence of hypertension; prevalence of diabetes; cholesterol, triglyceride, high-sensitivity C-reactive protein (CRP), leptin and fasting glucose levels; homeostatic model assessment of insulin resistance index (HOMA-IR); coronary artery calcium score; visceral adipose tissue; abdominal subcutaneous adipose tissue; and lower body subcutaneous adipose tissue. Cardiovascular events were comparable across groups defined by tertile of baseline liver fat content. Change in BMI (R=0.40), waist circumference (R=0.35), CRP (R=0.31), alanine aminotransferase (R=0.27), HOMA-IR (R=0.26), aspartate transaminase (R=0.15) and triglycerides (R=0.12) significantly correlated with change in liver fat content (P < 0.01 for all). Clinically relevant metabolic abnormalities were higher across quintiles of liver fat, with increases noted well within normal liver fat ranges, but cardiovascular events were not associated with liver fat content. Longitudinal changes in metabolic parameters, especially adiposity-related parameters, were correlated with change in liver fat content.

Clinical Intervention to Reduce Dietary Sugar Does Not Affect Liver Fat in Latino Youth, Regardless of PNPLA3 Genotype: A Randomized Controlled Trial

Nonalcoholic fatty liver disease (NAFLD) among Latinos is partially attributed to a prevalent C>G polymorphism in the patatin-like phospholipase 3 (PNPLA3) gene. Cross-sectional analyses in Latino children showed the association between dietary sugar and liver fat was exacerbated by GG genotype. Pediatric feeding studies show extreme sugar restriction improves liver fat, but no prior trial has examined the impact of a clinical intervention or whether effects differ by PNPLA3 genotype. We aimed to test effects of a clinical intervention to reduce dietary sugar compared with standard dietary advice on change in liver fat, and secondary-endpoint changes in liver fibrosis, liver enzymes, and anthropometrics; and whether effects differ by PNPLA3 genotype (assessed retrospectively) in Latino youth with obesity (BMI≥95th percentile). This parallel-design trial randomly assigned participants (n=105; mean baseline liver fat: 12.7%; mean age: 14.8 y) to control or sugar reduction (goal of ≤10% of calories from free sugar) for 12 wk. Intervention participants met with a dietitian monthly and received delivery of bottled water. Changes in liver fat, by MRI, were assessed by intervention group via general linear models. Mean free sugar intake decreased in intervention compared with control [11.5% to 7.3% compared with 13.9% to 10.7% (% energy), respectively; P=0.02], but there were no significant effects on liver outcomes or anthropometrics (Pall>0.10), and no PNPLA3 interactions (Pall>0.10). In exploratory analyses, participants with whole-body fat mass (FM) reduction (mean±SD: -1.9±2.4kg), irrespective of randomization, had significant reductions in liver fat compared with participants without FM reduction (median: -2.1%; IQR: -6.5% to -0.8% compared with 0.3%; IQR: -1.0% to 1.1%; P<0.001). In Latino youth with obesity, a dietitian-led sugar reduction intervention did not improve liver outcomes compared with control, regardless of PNPLA3 genotype. Results suggest FM reduction is important for liver fat reduction, confirming clinical recommendations of weight loss and a healthy diet for pediatric NAFLD.This trial was registered at clinicaltrials.gov as NCT02948647.

Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations.

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) is highly prevalent in people with diabetes with no available treatment. AIMTo explore the effect of testosterone treatment on liver. Testosterone therapy improves insulin resistance and reduces total body fat, but its impact on the liver remains poorly studied.METHODSThis secondary analysis of a 40 wk, randomised, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in men with type 2 diabetes and lowered serum testosterone concentrations evaluated the change in hepatic steatosis as measured by liver fat fraction on magnetic resonance imaging (MRI).RESULTSOf 88 patients enrolled in the index study, 39 had liver MRIs of whom 20 received testosterone therapy and 19 received placebo. All patients had > 5% hepatic steatosis at baseline and 38 of 39 patients met diagnostic criteria for NAFLD. Median liver fat at baseline was 15.0% (IQR 11.5%-21.1%) in the testosterone and 18.4% (15.0%-28.9%) in the placebo group. Median ALT was 34units/L (26-38) in the testosterone and 32units/L (25-52) in the placebo group. At week 40, patients receiving testosterone had a median reduction in absolute liver fat of 3.5% (IQR 2.9%-6.4%) compared with an increase of 1.2% in the placebo arm (between-group difference 4.7% P < 0.001). After controlling for baseline liver fat, testosterone therapy was associated with a relative reduction in liver fat of 38.3% (95% confidence interval 25.4%-49.0%, P < 0.001). CONCLUSIONTestosterone therapy was associated with a reduction in hepatic steatosis in men with diabetes and low serum testosterone. Future randomised studies of testosterone therapy in men with NAFLD focusing on liver-related endpoints are therefore justified.

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study

AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD). STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites. Patients aged 18-75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov, NCT03763877. Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was -1·1% in the placebo group, -1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI -15·4 to 15·7], p=0·99), -14·3% in the 250 mg twice daily group (-13·1% [-28·1 to 1·8], p=0·084), and -14·7% in the 500 mg once daily group (-13·5% [-28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred. PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis. Poxel.

Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism

BackgroundPioglitazone is a promising therapeutic method for nonalcoholic fatty liver disease (NAFLD) patients with or without type 2 diabetes. However, there is remarkable variability in treatment response. We analyzed our previous randomized controlled trial to examine the effects of gender and other factors on the efficacy of pioglitazone in treating Chinese nonalcoholic fatty liver disease (NAFLD) patients with abnormal glucose metabolism.MethodsThis is a post hoc analysis of a previous randomized, parallel controlled, open-label clinical trial (RCT) with an original purpose of evaluating the efficacy of berberine and pioglitazone on NAFLD. The total population (n = 185) was randomly divided into three groups: lifestyle intervention (LSI), LSI + pioglitazone (PGZ) 15 mg qd, and LSI + berberine (BBR) 0.5 g tid, respectively, for 16 weeks. The study used proton magnetic resonance spectroscopy (1H-MRS) to assess liver fat content.ResultsAs compared with LSI, PGZ + LSI treatment further decreased liver fat content in women (− 15.24% ± 14.54% vs. − 8.76% ± 13.49%, p = 0.025), but less decreased liver fat content in men (− 9.95% ± 15.18% vs. − 12.64% ± 17.78%, p = 0.046). There was a significant interaction between gender and efficacy of pioglitazone before and after adjustment for age, smoking, drinking, baseline BMI, BMI change, treatment adherence, baseline liver fat content, and glucose metabolism.ConclusionThe study recommends pioglitazone plus lifestyle intervention for Chinese NAFLD female patients with abnormal glucose metabolism.Trial registrationRole of Pioglitazone and Berberine in Treatment of Non-Alcoholic Fatty Liver Disease, NCT00633282. Registered on 3 March 2008, https://register.clinicaltrials.gov.

LPCN 1144 Resolves NAFLD in Hypogonadal Males

Hypogonadism affects hepatic lipid metabolism and is expected to promote nonalcoholic fatty liver disease (NAFLD). The aims of this study were to determine (1) the prevalence of NAFLD in hypogonadal males and (2) the impact of correction of hypogonadism by LPCN 1144 (Lipocine, Inc., Salt Lake City, UT), an oral testosterone prodrug, on NAFLD in this population. Data were derived from a multicenter open‐label single‐arm trial of LPCN 1144 for hypogonadal males, in which a subset (n = 36) had serial magnetic resonance imaging–proton density fat fraction measurements (National Clinical Trial 03868059). NAFLD prevalence, defined by magnetic resonance imaging–proton density fat fraction ≥5%, was 66%. Eighty‐one percent of those with baseline liver fat (BL) ≥5% had improvement in liver fat content, and NAFLD resolved in 33% of subjects at 8 weeks (mean relative reduction: 45%) and 48% (mean relative reduction: 55%) after 16 weeks of LPCN 1144 therapy. The reduction in liver fat was greater in those with higher BL (BL ≥5%: 71%; BL ≥8%: 80%; and BL ≥10%: 75%). Normalization rate of alanine aminotransferase and gamma‐glutamyltransferase greater than the upper limit of normal range were 100% and 50% of treated patients, respectively. LPCN 1144 was not associated with major adverse events. Conclusion: Treatment with LPCN 1144 (oral T prodrug) in hypogonadal males with NAFLD resolved NAFLD in approximately half of the affected patients without any safety signals. Further studies are needed to validate its use in hypogonadal males with nonalcoholic steatohepatitis.

Hydrogen-rich water reduces liver fat accumulation and improves liver enzyme profiles in patients with non-alcoholic fatty liver disease: a randomized controlled pilot trial

While non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide, its treatment remains elusive. Since metabolic impairment plays a major role in NAFLD pathogenesis, any pharmaceuticals, such as molecular hydrogen (H2), that advance lipid and glucose metabolism could be appropriate to tackle this complex condition. The aim of this study was to analyze the effects of 28-day hydrogen-rich water intake on liver fat deposition, body composition and lab chemistry profiles in overweight patients suffering from mild-to-moderate NAFLD. Twelve overweight outpatients with NAFLD (age 56.2 ± 10.0 years; body mass index 37.7 ± 5.3 kg/m2; 7 women and 5 men) voluntarily participated in this double-blind, placebo-controlled, crossover trial. All patients were allocated to receive either 1 L per day of hydrogen-rich water (HRW) or placebo water for 28 days. The study was registered at ClinicalTrials.gov (ID NCT03625362). Dual-echo MRI revealed that HRW significantly reduced liver fat accumulation in individual liver regions-of-interest at 28-day follow-up, as compared to placebo administration (P < 0.05). Baseline liver fat content was reduced from 284.0 ± 118.1 mM to 256.5 ± 108.3 mM after hydrogen treatment at 28-day follow-up (percent change 2.9%; 95% CI from 0.5 to 5.5). Serum aspartate transaminase levels dropped by 10.0% (95% CI; from -23.2 to 3.4) after hydrogen treatment at 28-day follow-up. No significant differences were observed between treatment groups in either weight or body composition among participants. Although preliminary, the results of this trial perhaps nominate HRW as an adjuvant treatment for mild-to-moderate NAFLD. These observations provide a rationale for further clinical trials to establish safety and efficacy of molecular hydrogen in NAFLD.

Effect of Fish Oil Supplementation on Hepatic and Visceral Fat in Overweight Men: A Randomized Controlled Trial.

Being overweight increases the risk of the development of metabolic conditions such as non-alcoholic fatty liver disease (NAFLD), which is itself an independent predictor of cardiovascular disease. Omega-3 polyunsaturated fatty acid (PUFA) supplementation is recommended for prevention of chronic disease, and is thought to reduce raised liver fat, yet there have been few randomized controlled trials with accurate measurement of liver fat. We assessed the effect of 12 weeks of supplementation with omega-3 PUFA from fish oil versus placebo on quantified liver fat, liver tests, and body composition including visceral adipose tissue (VAT) in a double-blind randomized controlled trial. Fifty apparently healthy overweight men (BMI 25.0–29.9 kg/m2; waist > 94 cm) were randomly allocated to consume fish oil (total daily dose: 1728 mg marine triglycerides, of which 588 mg EPA and 412 mg DHA, combined with 200 mg antioxidant, coenzyme Q10) or placebo (olive oil capsules) daily for 12 weeks. Liver fat was assessed using proton magnetic resonance spectroscopy. All outcomes were assessed at baseline and following 6 and 12 weeks of supplementation. Baseline liver fat was 4.6 ± 0.5% (range: 0.6 to 18.2%); 16 (32%) participants met the criteria for NAFLD (>5.5% liver fat). Repeated measures ANOVA revealed no significant time or group × time effect for fish oil versus placebo for liver fat, liver enzymes, anthropometry, or body composition including VAT (p > 0.05 for all), with similar finding for sub-analysis of participants with NAFLD. Omega-3 PUFA did not appear to be an effective agent for reducing liver fat in overweight men. The factors determining the health benefits of omega-3 PUFA supplementation on an individual level need to be clarified.

Magnetic resonance imaging fatty liver changes following surgical, lifestyle or drug treatments in obese, non-alcoholicfatty liver disease or non-alcoholic steatohepatitis subjects

With an increasing insulin resistance and obesity epidemic, various intervention trials aiming to reduce liver fat levels are using non-invasive MRI methods as alternatives to repeated biopsies to measure the changes in liver fat levels in controlled clinical trials. MRI and MRS exploit differences in the resonance frequencies of signals from protons in fat and water to quantify liver, fat depot and/or muscle fractional fat content in a highly reproducible manner. Various clinical trials have reported the baseline liver fat values and ranges along with the changes in fat levels following different surgical, nutritional, lifestyle or pharmaceutical interventions.

Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) \u2013 an 11-Year Prospective Study

Liver fat can be non-invasively measured by proton magnetic resonance spectroscopy (1H-MRS) and fibrosis estimated as stiffness using transient elastography (FibroScan). There are no longitudinal data on changes in liver fat in Europids or on predictors of liver stiffness using these methods. We determined liver fat (1H-MRS) and clinical characteristics including features of insulin resistance at baseline and after a median follow-up period of 11.3 (range 7.3–13.4) years in 97 Finnish subjects. Liver stiffness was measured at 11.3 years. Liver fat content decreased by 5% (p < 0.05) over time. Values at baseline and 11.3 years were closely interrelated (r = 0.81, p < 0.001). Baseline liver fat (OR 1.32; 95%CI: 1.15–1.50) and change in BMI (OR 1.67; 95%CI: 1.24–2.25) were independent predictors of liver fat at 11.3 years (AUROC 0.90; 95%CI: 0.83–0.96). Baseline liver fat (AUROC 0.84; 95%CI: 0.76–0.92) predicted liver fat at 11.3 years more accurately than routinely available parameters (AUROC 0.76; 95%CI: 0.65–0.86, p = 0.02). At 11.3 years, 29% of the subjects had increased liver stiffness. Baseline liver fat (OR 2.17; 95%CI: 1.05–4.46) was an independent predictor of increased liver stiffness. These data show that liver fat is more important than the associated metabolic abnormalities as the predictor of future liver fat and fibrosis.

Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity

Consumption of sugar is associated with obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis [DNL]) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/d). Children (9-18 years old; n= 41) had all meals provided for 9 days with the same energy and macronutrient composition as their standard diet, but with starch substituted for sugar, yielding a final fructose content of 4% of total kilocalories. Metabolic assessments were performed before and after fructose restriction. Liver fat, VAT, and subcutaneous fat were determined by magnetic resonance spectroscopy and imaging. The fractional DNL area under the curve value was measured using stable isotope tracers and gas chromatography/mass spectrometry. Insulin kinetics were calculated from oral glucose tolerance tests. Paired analyses compared change from day 0 to day 10 within each child. Compared with baseline, on day 10, liver fat decreased from a median of 7.2% (interquartile range [IQR], 2.5%-14.8%) to 3.8% (IQR, 1.7%-15.5%) (P < .001) and VAT decreased from 123 cm3 (IQR, 85-145 cm3) to 110 cm3 (IQR, 84-134 cm3) (P < .001). The DNL area under the curve decreased from 68% (IQR, 46%-83%) to 26% (IQR, 16%-37%) (P < .001). Insulin kinetics improved (P < .001). These changes occurred irrespective of baseline liver fat. Short-term (9 days) isocaloric fructose restriction decreased liver fat, VAT, and DNL, and improved insulin kinetics in children with obesity. These findings support efforts to reduce sugar consumption. ClinicalTrials.gov Number: NCT01200043.

Impact of weight loss-associated changes in detailed body composition as assessed by whole-body MRI on plasma insulin levels and homeostatis model assessment index

We assessed the effect of weight loss-associated changes in detailed body composition on plasma insulin levels and homeostatic model assessment (HOMA) index to calculate the magnitude of reduction in different adipose tissue depots required to improve insulin sensitivity. A total of 50 subjects aged 20-69 years were studied. The participants were compiled from low-calorie diet interventions and bariatric surgery and differed in their baseline body mass index (BMI; range 21.6-54.4 kg/m2) and degree of weight losses (range -3.3 to -56.9 kg). Detailed body composition and liver fat were measured using whole-body magnetic resonance imaging (MRI). Insulin resistance was assessed by HOMA. Mean body weight decreased by -16.0±13.6 kg. Significant changes were observed in total adipose tissue (TATMRI, range -0.5 to -36.0 kg), total subcutaneous adipose tissue (SATMRI), visceral adipose tissue (VATMRI), skeletal muscle, liver fat, plasma insulin levels and HOMA. Decreases in insulin and HOMA were correlated with reductions in TATMRI, SATMRI, VATMRI (just with HOMA) and liver fat. Losses of 2.9 and 6.5 kg body weight, 2.0 and 5.0 kg TATMRI as well as 1.6 and 6% liver fat were required to decrease plasma insulin levels by 1 μU/ml and HOMAadjusted for baseline HOMA by 1 point. Multiple regression analysis showed that baseline liver fat and changes in liver fat explained 49.7% and 55.1% of the variance in weight loss-associated changes in plasma insulin and HOMA, respectively. Decreases of adipose tissues and liver fat are the major determinants of reduction in plasma insulin levels and improvement in HOMA index.

Bi-directional analysis between fatty liver and cardiovascular disease risk factors

The relations of non-alcoholic fatty liver disease to cardiovascular disease (CVD) risk factors are not fully understood. The objective of our study is to explore the bi-directional relationships of fatty liver to CVD risk factors. We prospectively evaluated whether liver fat predicted the development of CVD risk factors and whether CVD risk factors predicted new onset fatty liver during 6years of follow-up in middle- to older-aged Framingham Heart Study participants. We estimated liver fat using multi-detector computed tomography. We included 1051 participants (mean age 45±6years, 46% women). The prevalence of fatty liver was 18% at baseline. In participants without fatty liver at baseline, 101 participants developed incident fatty liver over approximately 6years. Baseline liver fat (per standard deviation increase) was associated with increased odds of incident hypertension (OR 1.42; 95% CI 1.15-1.76; p=0.001) and incident type 2 diabetes (OR 1.43; 95% CI 1.09-1.88, p<0.001). In a parallel analysis, individuals with hypertension (OR 3.34; 95% CI 2.04-5.49), hypertriglyceridemia (OR 3.04; 95% CI: 1.84-5.02), impaired fasting glucose (OR 2.92; 95% CI 1.76-4.82), or type 2 diabetes (OR 4.15; 95% CI 1.19-14.46) at baseline had higher odds of incident fatty liver compared to individuals without those conditions (all p<0.03). In both analyses, the observed associations remained similar after additional adjustments for measures of adiposity. The present study demonstrated bi-directional relationships between fatty liver and CVD risk factors among middle- to older-aged Framingham Heart Study participants. It is not fully understood whether non-alcoholic fatty liver (NAFLD) disease precedes or develops after increased cardiovascular disease (CVD) risk factors. The findings of our study suggest a bi-directional relationship between NAFLD and CVD risk factors.

Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver

Guidelines about recommendations for amounts of exercise/physical activity are variable in non-alcoholic fatty liver disease. Our aim was to determine the amount of exercise that was associated with two outcomes: a) development of incident liver fat and b) resolution of baseline liver fat, at five-year follow-up. In an occupational health screening program, weekly frequency of exercise was assessed using the validated Korean version of the International Physical Activity Questionnaire Short Form (IPAQ-SF). Liver fat was identified by ultrasonography (3.5MHz probe) at baseline and at five-year follow-up. Fully adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs and 95% confidence intervals [CI]) for incident fatty liver and resolution of fatty liver at follow-up. 233,676 men and women were studied between 2002 and 2014. 126,811 individuals were identified without fatty liver, and of these subjects, 29,014 subjects developed incident fatty liver during follow-up. At baseline, there were 42,536 individuals with liver fat and of these individuals, fatty liver resolved in 14,514, during follow-up. After full adjustment, compared to no exercise, exercise was associated with benefit for both outcomes; for exercise ⩾5times per week for incident fatty liver: HR 0.86 (95% CI 0.80,0.92), p<0.001, and for resolution of fatty liver HR 1.40 (95% CI 1.25,1.55), p<0.001. Moderate to vigorous exercise is beneficial in decreasing risk of development of new fatty liver or improving resolution of existing fatty liver during 5years of follow-up. The amount of exercise/physical activity to benefit fatty liver disease in non-alcoholic fatty liver disease is not known. In a large study of free-living people, our aim was to determine the amount of exercise that was linked with a decrease in new fatty liver and also improvement of existing fatty liver over 5years of follow-up. Compared to no exercise, exercise ⩾5times per week (lasting at least 10min on each occasion) was linked to a highly significantly benefit for both a decrease in new fatty liver and also improvement of existing fatty liver.

Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients

Niacin reduces plasma triglycerides, but it may increase free fatty acids and insulin resistance during long-term treatment. We examined the effect of extended-release niacin on liver fat content in Chinese patients with dyslipidemia and whether the common diacylglycerol acyltransferase-2 (DGAT2) polymorphisms influenced this effect. The 39 patients (baseline liver fat content: 12.8 ± 7.6%, triglycerides: 3.30 ± 1.67 mmol/l) were treated with niacin, gradually increasing the dose to 2 g/day for a total of 23 weeks. The liver fat content and visceral/subcutaneous fat was measured before and after treatment. Subjects were genotyped for the DGAT2 rs3060 and rs101899116 polymorphisms. There were significant (P < 0.001) reductions in plasma triglycerides (-34.9 ± 37.6%), liver fat content (-47.2 ± 32.8%), and visceral fat (-6.3 ± 15.8%, P < 0.05) after niacin treatment. Mean body weight decreased by 1.46 ± 2.7% (1.17 ± 2.44 kg, P < 0.001) during the study, but liver fat changes remained significant after adjustment for age, gender, and body weight changes [mean absolute change (95% CI): -6.1% (-8.0, -4.3), P < 0.001]. The DGAT2 variant alleles were associated with a smaller reduction in liver fat content in response to niacin after adjustment for other covariates (P < 0.01). These findings suggest that niacin treatment may reduce liver fat content in Chinese patients with dyslipidemia and that the mechanism may involve inhibition of DGAT2. However, the findings might have been confounded by the small but significant reductions in body weight during the study. Future large randomized controlled trials are needed to verify these findings.

Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content.

Our objective was to determine how 8% weight loss influences subcutaneous, intra-abdominal, and liver fat (LFAT), as well as features of insulin resistance, in obese women with high versus low LFAT. A total of 23 women with previous gestational diabetes were divided into groups of high (9.4 +/- 1.4%) and low (3.3 +/- 0.4%) LFAT based on their median LFAT (5%) measured with proton spectroscopy. Both groups were similar with respect to age, BMI, and intra-abdominal and subcutaneous fat. Before weight loss, women with high LFAT had higher fasting serum insulin and triglyceride concentrations than women with low LFAT. At baseline, LFAT correlated with the percent of fat (r = 0.44, P < 0.05) and saturated fat (r = 0.45, P < 0.05) of total caloric intake but not intra-abdominal or subcutaneous fat or fasting serum free fatty acids. Weight loss was similar between the groups (high LFAT -7.4 +/- 0.2 vs. low LFAT -7.7 +/- 0.3 kg). LFAT decreased from 9.4 +/- 1.4 to 4.8 +/- 0.7% (P < 0.001) in women with high LFAT and from 3.3 +/- 0.4 to 2.0 +/- 0.2% (P < 0.001) in women with low LFAT. The absolute decrease in LFAT was significantly higher in women with high than low LFAT (-4.6 +/- 1.0 vs. -1.3 +/- 0.3%, P < 0.005). The decrease in LFAT was closely correlated with baseline LFAT (r = -0.85, P < 0.001) but not with changes in the volumes of intra-abdominal or subcutaneous fat depots, which decreased similarly in both groups. LFAT appears to be related to the amount of fat in the diet rather than the size of endogenous fat depots in obese women. Women with initially high LFAT lost more LFAT by similar weight loss than those with low LFAT, although both groups lost similar amounts of subcutaneous and intra-abdominal fat. These data suggest that LFAT is regulated by factors other than intra-abdominal and subcutaneous fat. Therefore, LFAT does not appear to simply reflect the size of endogenous fat stores.