Ran Jin

Children with NAFLD Are More Sensitive to the Adverse Metabolic Effects of Fructose Beverages than Children without NAFLD

CONTEXT Dietary fructose induces unfavorable lipid alterations in animal models and adult studies. Little is known regarding metabolic tolerance of dietary fructose in children. OBJECTIVES The aim of the study was to evaluate whether dietary fructose alters plasma lipids in children with nonalcoholic fatty liver disease (NAFLD) and in healthy children. DESIGN AND SETTING We performed a 2-d, crossover feeding study at the Inpatient Clinical Interaction Site of the Atlanta Clinical and Translational Science Institute at Emory University Hospital. PARTICIPANTS AND INTERVENTION Nine children with NAFLD and 10 matched controls without NAFLD completed the study. We assessed plasma lipid levels over two nonconsecutive, randomly assigned, 24-h periods under isocaloric, isonitrogenous conditions with three macronutrient-balanced, consecutive meals and either: 1) a fructose-sweetened beverage (FB); or 2) a glucose beverage (GB) being consumed with each meal. MAIN OUTCOME MEASURES Differences in plasma glucose, insulin, triglyceride, apolipoprotein B, high-density lipoprotein cholesterol, and nonesterified free fatty acid levels were assessed using mixed models and 24-h incremental areas under the time-concentration curve. RESULTS After FB, triglyceride incremental area under the curve was higher vs. after GB both in children with NAFLD (P = 0.011) and those without NAFLD (P = 0.027); however, incremental response to FB was greater in children with NAFLD than those without NAFLD (P = 0.019). For all subjects, high-density lipoprotein cholesterol declined in the postprandial and overnight hours with FB, but not with GB (P = 0.0006). Nonesterified fatty acids were not impacted by sugar but were significantly higher in NAFLD. CONCLUSIONS The dyslipidemic effect of dietary fructose occurred in both healthy children and those with NAFLD; however, children with NAFLD demonstrated increased sensitivity to the impact of dietary fructose.

Dietary Fructose Reduction Improves Markers of Cardiovascular Disease Risk in Hispanic-American Adolescents with NAFLD

Nonalcoholic fatty liver disease (NAFLD) is now thought to be the most common liver disease worldwide. Cardiovascular complications are a leading cause of mortality in NAFLD. Fructose, a common nutrient in the westernized diet, has been reported to be associated with increased cardiovascular risk, but its impact on adolescents with NAFLD is not well understood. We designed a 4-week randomized, controlled, double-blinded beverage intervention study. Twenty-four overweight Hispanic-American adolescents who had hepatic fat >8% on imaging and who were regular consumers of sweet beverages were enrolled and randomized to calorie-matched study-provided fructose only or glucose only beverages. After 4 weeks, there was no significant change in hepatic fat or body weight in either group. In the glucose beverage group there was significantly improved adipose insulin sensitivity, high sensitivity C-reactive protein (hs-CRP), and low-density lipoprotein (LDL) oxidation. These findings demonstrate that reduction of fructose improves several important factors related to cardiovascular disease despite a lack of measurable improvement in hepatic steatosis. Reducing dietary fructose may be an effective intervention to blunt atherosclerosis progression among NAFLD patients and should be evaluated in longer term clinical trials.

Fructose Induced Endotoxemia in Pediatric Nonalcoholic Fatty Liver Disease

In preclinical studies of fructose-induced NAFLD, endotoxin appears to play an important role. We retrospectively examined samples from three pediatric cohorts (1) to investigate whether endotoxemia is associated with the presence of hepatic steatosis; (2) to evaluate postprandial endotoxin levels in response to fructose beverage in an acute 24-hour feeding challenge, and (3) to determine the change of fasting endotoxin amounts in a 4-week randomized controlled trial comparing fructose to glucose beverages in NAFLD. We found that adolescents with hepatic steatosis had elevated endotoxin levels compared to obese controls and that the endotoxin level correlated with insulin resistance and several inflammatory cytokines. In a 24-hour feeding study, endotoxin levels in NAFLD adolescents increased after fructose beverages (consumed with meals) as compared to healthy children. Similarly, endotoxin was significantly increased after adolescents consumed fructose beverages for 2 weeks and remained high although not significantly at 4 weeks. In conclusion, these data provide support for the concept of low level endotoxemia contributing to pediatric NAFLD and the possible role of fructose in this process. Further studies are needed to determine if manipulation of the microbiome or other methods of endotoxin reduction would be useful as a therapy for pediatric NAFLD.

Amount of hepatic fat predicts cardiovascular risk independent of insulin resistance among Hispanic-American adolescents

BackgroundNonalcoholic fatty liver disease (NAFLD) has emerged as the major pediatric chronic liver disease, and it is estimated to affect more than one third of obese children in the U.S. Cardiovascular complications are a leading cause of increased mortality in adults with NAFLD and many adolescents with NAFLD already manifest signs of subclinical atherosclerosis including increased carotid intima-media thickness.MethodsVolume of intrahepatic fat was assessed in 50 Hispanic-American, overweight adolescents, using Magnetic Resonance Spectroscopy. Lipoprotein compositions were measured using Nuclear Magnetic Resonance.ResultsPlasma triglycerides (TG) (p = 0.003), TG/HDL ratio (p = 0.006), TG/apoB ratio (p = 0.011), large VLDL concentration (p = 0.019), VLDL particle size (p = 0.012), as well as small dense LDL concentration (p = 0.026) progressively increased across higher levels of hepatic fat severity, while large HDL concentration progressively declined (p = 0.043). This pattern of associations remained even after controlling for gender, BMI, visceral fat, and insulin resistance.ConclusionsOur findings suggest that increased hepatic fat is strongly associated with peripheral dyslipidemia and the amount of fat in the liver may influence cardiovascular risk. Further studies are needed to longitudinally monitor dyslipidemia in children with NAFLD and to examine whether the reduction of hepatic fat would attenuate their long-term CVD risk.

Fructose and liver function--is this behind nonalcoholic liver disease?

Purpose of reviewThe purpose was to summarize recent advances in the understanding of nonalcoholic fatty liver disease (NAFLD) pathophysiology and the role of fructose in NAFLD. Recent findingsEpidemiological studies continue to point to a strong association between high fructose intake and NAFLD and its severity. New studies of NAFLD reveal the importance of upregulated de novo lipogenesis as a key feature in its pathophysiology along with increased visceral adiposity and alteration of gut microbiome. Studies of fructose in NAFLD show how this nutrient may uniquely exacerbate the phenotype of NAFLD. The timing of exposure to fructose may be important with early (in utero) exposure being particularly harmful. SummaryFructose is a potentially modifiable environmental exposure that appears to exacerbate NAFLD through multiple mechanisms. Although larger, longer clinical studies are still needed, it appears that limitation of fructose sources in the diet is beneficial in NAFLD.

Changes in Lipoprotein Particle Number With Ezetimibe/Simvastatin Coadministered With Extended-Release Niacin in Hyperlipidemic Patients

Background Combination therapy with ezetimibe/simvastatin (E/S) and extended‐release niacin (N) has been reported to be safe and efficacious in concomitantly reducing low‐density lipoprotein cholesterol and increasing high‐density lipoprotein cholesterol in hyperlipidemic patients at high risk for atherosclerotic cardiovascular events. This analysis evaluated the effect of E/S coadministered with N on low‐density lipoprotein particle number (LDL‐P) and high‐density lipoprotein particle number (HDL‐P) as assessed by nuclear magnetic resonance (NMR) spectroscopy in patients with type IIa or IIb hyperlipidemia. Methods and Results This was an analysis of a previously reported 24‐week randomized, double‐blind study in type IIa/IIb hyperlipidemic patients randomized to treatment with E/S (10/20 mg/day)+N (titrated to 2 g/day) or N (titrated to 2 g/day) or E/S (10/20 mg/day). Samples from a subset of patients (577 of 1220) were available for post hoc analysis of LDL‐P and HDL‐P by NMR spectroscopy. Increases in HDL‐P (+16.2%) and decreases in LDL‐P (−47.7%) were significantly greater with E/S+N compared with N (+9.8% for HDL‐P and −21.5% for LDL‐P) and E/S (+12.8% for HDL‐P and −36.8% for LDL‐P). In tertile analyses, those with the lowest baseline HDL‐P had the greatest percent increase in HDL‐P (N, 18.4/7.9/2.1; E/S, 19.3/12.2/5.3; and E/S+N, 26.9/13.8/6.9; all P<0.001). Individuals in the highest tertile of LDL‐P had the greatest percent reduction in LDL‐P (N, 18.3/23.1/24.6; E/S, 29.7/38.3/41.8; and E/S+N, 44.3/49.0/50.5; all P<0.001). Conclusions These results suggest that E/S+N improves lipoprotein particle number, consistent with its lipid‐modifying benefits in type IIa or IIb hyperlipidemia patients and may exert the greatest effect in those with high LDL‐P and low HDL‐P at baseline. Clinical Trial Registration URL: Clinicaltrials.gov Identifier: NCT00271817

Association between plasminogen activator inhibitor-1 and severity of liver injury and cardiovascular risk in children with non-alcoholic fatty liver disease.

Plasminogen activator inhibitor‐1 (PAI‐1) is the primary inhibitor of the endogenous fibrinolytic system and is known to be increased in obesity, insulin resistance and non‐alcoholic fatty liver disease (NAFLD). We previously demonstrated that PAI‐1 levels were closely related to the amount of hepatic steatosis in children.

Performance of fibrosis prediction scores in paediatric non-alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. The phenotype of NAFLD varies widely, and non‐invasive predictors of disease severity are scarce and are needed to tailor clinical management.

Cardiometabolic risks vary by weight status in pediatric kidney and liver transplant recipients: A cross‐sectional, single‐center study in the USA

There is an increasing need to understand long‐term metabolic changes and resultant comorbidities because life expectancy is increasing after pediatric kidney and liver transplants. We evaluated differences in classic and novel cardiometabolic biomarkers among obese and normal weight adolescent transplant recipients. We enrolled a total of 80 adolescent (mean±SD, 14.8 years ±3.0) transplant recipients (63 kidney, 17 liver) with mean duration from transplantation of 6.0 (±4.1) years. Among kidney transplant recipients, overweight and obese individuals had higher leptin (16.7 vs 7.5 μg/mL, P<.001), lower HDL (1.1 vs 1.3 mmol/L, P=.02), higher free fatty acid (0.6 vs 0.5 mmol/L, P=.03), higher apoB‐to‐apoA1 ratio (0.8 vs 0.6, P=.03), and higher glucose (5.8 vs 4.3 mmol/L, P=.03) concentrations compared to normal weight individuals. Regardless of obesity status, over half of all participants (57.5%) were considered at high cardiometabolic risk using consensus guidelines, and this was more pronounced for kidney transplant recipients (61.9%). Post‐transplantation adolescents have increased cardiometabolic risk characterized by traditional risk factors of obesity and diabetes. The presence of obesity significantly worsens biomarkers of cardiometabolic risk. Future studies should explore whether treatment of obesity can improve the health and long‐term outcomes for children undergoing solid organ transplant.

Role of PAI-1 in Pediatric Obesity and Nonalcoholic Fatty Liver Disease

Purpose of ReviewThe purpose of this study is to review the role of plasminogen activator inhibitor-1 (PAI-1) in pediatric obesity and nonalcoholic fatty liver disease (NAFLD).Recent FindingsOngoing evidence supports that patients with insulin resistance, obesity, NAFLD, and cardiovascular disease have higher levels of PAI-1. The role of PAI-1 in NAFLD has been further delineated and both experimental models and human studies strongly support an independent role of PAI-1 in the pathophysiology of NAFLD.SummaryGrowing evidence supports a mechanistic role of PAI-1 in obesity associated metabolic abnormalities including NAFLD and its long-term association with CVD. Reduction of PAI-1 could be a promising therapeutic strategy for both ongoing hepatic injury and reduction of associated cardiovascular risk.