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Proteomic characterization of high-density lipoprotein particles in patients with non-alcoholic fatty liver disease.

ABSTRACT: Background:Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications. Methods:From a cohort of morbidly obese females who were diagnosed with simple steatosis (SS), NASH, or normal liver histology, we selected five matched individuals from each condition for a preliminary pilot HDL proteome analysis. HDL particles were enriched using size-exclusion chromatography, and the proteome of the resulting fraction was analyzed by liquid chromatography tandem mass spectrometry. Differences in the proteomes between the three conditions (normal, SS, NASH) were assessed using label-free quantitative analysis. Gene ontology term analysis was performed to assess the potential impact of proteomic changes on specific functions of HDL particles. Results:Of the 95 proteins identified, 12 proteins showed nominally significant differences between the three conditions. Gene ontology term analysis revealed that severity of the liver pathology may significantly impact the anti-thrombotic functions of HDL particles, as suggested by changes in the abundance of HDL-associated proteins such as antithrombin III and plasminogen. Conclusions:The pilot data from this study suggest that changes in the HDL proteome may impact the functionality of HDL particles in NAFLD and NASH patients. These proteome changes may alter cardio-protective properties of HDL, potentially contributing to the increased cardiovascular disease risk in affected individuals. Further validation of these protein changes by orthogonal approaches is key to confirming the role of alterations in the HDL proteome in NAFLD and NASH. This will help elucidate the mechanistic effects of the altered HDL proteome on cardioprotective properties of HDL particles.

SUBMITTER: Rao PK

PROVIDER: S-EPMC5839024 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Proteomic characterization of high-density lipoprotein particles in patients with non-alcoholic fatty liver disease.

Rao Prahlad K PK Merath Kate K Drigalenko Eugene E Jadhav Avinash Y L AYL Komorowski Richard A RA Goldblatt Matthew I MI Rohatgi Anand A Sarzynski Mark A MA Gawrieh Samer S Olivier Michael M

Clinical proteomics 20180306

<h4>Background</h4>Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have in ...[more]

PMID: 29527140

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Project description:ObjectiveThe evidence for a relationship between the ratio of gamma-glutamyl transferase (GGT) to high-density lipoprotein cholesterol (HDL-c) and non-alcoholic fatty liver disease (NAFLD) is currently inadequate. This study aimed to investigate the relationship between the GGT/HDL-c ratio and NAFLD.Materials and methodsThis study is a prospective cohort study that recruited a total of 11,891 non-obese volunteers in a Chinese hospital from January 2010 to December 2014 in a non-selective manner. The Cox proportional-hazards regression model was then used to investigate the relationship between baseline GGT/HDL-c ratio and the probability of developing NAFLD. The non-linear link between the GGT/HDL-c ratio and NAFLD was identified using a Cox proportional hazards regression with cubic spline functions and smooth curve fitting (cubic spline smoothing). Furthermore, we conducted several sensitivity and subgroup analyses. Data had been uploaded to the DATADRYAD website.ResultsThe mean age of study participants was 43.29 ± 14.95 years old, and 6,502 (54.68%) were male. The median (interquartile ranges) of GGT/HDL-c ratio was 15.56 (10.73-23.84). During a median follow-up of 29.35 months, 2028 (17.05%) participants were diagnosed with NAFLD. After adjusting for covariates, the results showed that GGT/HDL-c ratio was positively associated with incident NAFLD (HR = 1.014, 95% CI 1.011-1.017). There was also a non-linear relationship between GGT/HDL-c ratio and NAFLD, and the inflection point of the GGT/HDL-c ratio was 20.35. The effect sizes (HR) on the left and right sides of the inflection point were 1.113 (95% CI 1.096, 1.130) and 1.003 (95% CI 1.000-1.007), respectively. Moreover, the sensitivity analysis demonstrated the robustness of our results. Subgroup analysis showed that GGT/HDL-c ratio was more strongly associated with incident NAFLD in triglyceride (TG) < 1.7 mmol/L participants. In contrast, the weaker association was probed in those with TG ≥ 1.7 mmol/L.ConclusionThe present study reveals a positive and non-linear relationship between the GGT/HDL-c ratio and NAFLD risk in a non-obese Chinese population. GGT/HDL-c ratio is strongly associated with NAFLD when GGT/HDL-c ratio is less than 20.35. Therefore, maintaining the GGT/HDL-c ratio lower than the inflection point is recommended from a treatment perspective.

Project description:Background & aimsRemnant lipoprotein cholesterol (RLP-C) is an atherogenic lipid profile associated with non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). With increased rates of CVD seen in adults with NAFLD, RLP-C has the potential to identify individuals with NAFLD who are at increased risk of CVD. This study examined in adolescents sex-different associations among RLP-C, NAFLD, and cardiometabolic risk factors, and whether RLP-C is associated with NAFLD beyond traditional cardiometabolic risk factors.MethodsAdolescents in the Raine Study had anthropometry, clinical, biochemistry and arterial stiffness measurements recorded at 17 years of age. Fatty liver, subcutaneous and visceral adipose thickness were assessed using abdominal ultrasound. Relationships among RLP-C, NAFLD, liver biochemistry, insulin resistance, adipokines, adiposity and arterial stiffness were assessed.ResultsNAFLD was diagnosed in 15.1% (19.6% females and 10.7% males) of adolescents. Increasing RLP-C levels were associated with increasing severity of hepatic steatosis and metabolic syndrome. Adolescents with NAFLD and serum RLP-C levels in the highest quartile compared with the lowest quartile, had higher serum leptin, homeostatic model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein, low-density-lipoprotein cholesterol, triglycerides, BMI, subcutaneous and visceral adipose thickness, systolic blood pressure and arterial stiffness, but lower adiponectin and high-density-lipoprotein cholesterol. Using multivariable logistic regression, RLP-C in the lowest quartile compared with the highest quartile was associated with 85% lower odds of NAFLD in males and 55% in females, after adjusting for waist circumference, leptin, ALT, adiponectin and HOMA-IR.ConclusionsThere is an association between RLP-C and NAFLD beyond traditional risk factors of adiposity and insulin resistance in adolescents. Although raised serum RLP-C levels were associated with the severity of hepatic steatosis and markers of cardiometabolic risk, lower serum RLP-C might reflect reduced cardiovascular risk.Lay summaryRemnant lipoprotein cholesterol (RLP-C) is a part of the blood cholesterol that is linked with heart disease and non-alcoholic fatty liver disease (NAFLD) in adults. In the Raine Study, teenagers with high RLP-C levels had more severe fat accumulation in their liver. Thus, RLP-C might be the hidden link between NAFLD and future risk of heart disease.

Dataset Information

Proteomic characterization of high-density lipoprotein particles in patients with non-alcoholic fatty liver disease.

Publications

Proteomic characterization of high-density lipoprotein particles in patients with non-alcoholic fatty liver disease.

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