Altered Fatty Acid Metabolism-Related Gene Expression in Liver from Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with NAFLD. Liver expression of key genes related to de novo FA synthesis (LXRα, SREBP1c, ACC1, FAS), FA uptake and transport (PPARγ, CD36, FABP4), FA oxidation (PPARα), and inflammation (IL6, TNFα, CRP, PPARδ) were assessed by RT-qPCR in 127 MO women with normal liver histology (NL, n = 13), simple steatosis (SS, n = 47) and non-alcoholic steatohepatitis (NASH, n = 67). Liver FAS mRNA expression was significantly higher in MO NAFLD women with both SS and NASH compared to those with NL (p = 0.003, p = 0.010, respectively). Hepatic IL6 and TNFα mRNA expression was higher in NASH than in SS subjects (p = 0.033, p = 0.050, respectively). Interestingly, LXRα, ACC1 and FAS expression had an inverse relation with the grade of steatosis. These results were confirmed by western blot analysis. In conclusion, our results indicate that lipogenesis seems to be downregulated in advanced stages of SS, suggesting that, in this type of extreme obesity, the deregulation of the lipogenic pathway might be associated with the severity of steatosis

Interleukin-17A Gene Expression in Morbidly Obese Women

Data from recent studies conducted in rodent models and humans suggest that interleukin-17A (IL-17A) plays a role in the induction of inflammation in adipose tissue during obesity. The aim of this study was to assess the gene expression of IL-17A in adipose tissue of morbidly obese patients. We used RT-PCR to evaluate the expression of IL-17A and several adipo/cytokines in the visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of 10 normal-weight control women (BMI < 25 kg/m2) and 30 morbidly obese women (MO, BMI > 40 kg/m2). We measured serum levels of IL-17A and adipo/cytokines in MO and normal weight women. IL-17A expression was significantly higher in VAT than in SAT in MO patients (p = 0.0127). It was very low in normal-weight controls in both VAT and SAT tissues. We found positive correlations between IL-17A and IL-6, lipocalin-2 and resistin in VAT of MO patients. The circulating level of IL-17A was higher in the normal-weight group than the MO patients (p = 0.032), and it was significantly related to adiponectin and TNFRII levels. In conclusion, IL-17A expression in VAT is increased in morbidly obese women, which suggests a link between obesity and innate immunity in low-grade chronic inflammation in morbidly obese women

Increased Circulating Levels of Alpha-Ketoglutarate in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease.

BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, ranging from simple steatosis to cirrhosis. However, simple steatosis (SS) and steatohepatitis (NASH) cannot yet be distinguished by clinical or laboratory features. The aim of this study was to assess the relationship between alpha-ketoglutarate and the degrees of NAFLD in morbidly obese patients. MATERIALS AND METHODS:We used a gas chromatography-quadruple time-of-flight-mass spectrometry analysis to quantify alpha-ketoglutarate in serum from normal-weight subjects (n = 30) and morbidly obese women (n = 97) with or without NAFLD. RESULTS:We found that serum levels of alpha-ketoglutarate were significantly higher in morbidly obese women than in normal-weight women. We showed that circulating levels of alpha-ketoglutarate were lower in lean controls and morbidly obese patients without NAFLD. We also found that alpha-ketoglutarate serum levels were higher in both SS and NASH than in normal liver of morbidly obese patients. However, there was no difference between SS and NASH. Moreover, we observed that circulating levels of alpha-ketoglutarate were associated with glucose metabolism parameters, lipid profile, hepatic enzymes and steatosis degree. In addition, diagnostic performance of alpha-ketoglutarate has been analyzed in NAFLD patients. The AUROC curves from patients with liver steatosis exhibited an acceptable clinical utility. Finally, we showed that the combination of biomarkers (AST, ALT and alpha-ketoglutarate) had the highest accuracy in diagnosing liver steatosis. CONCLUSION:These findings suggest that alpha-ketoglutarate can determine the presence of non-alcoholic fatty liver in morbidly obese patients but it is not valid a biomarker for NASH

Circulating levels of alpha-ketoglutarate in study cohort.

<p>Circulating levels of alpha-ketoglutarate in normal-weight controls and morbidly obese women (<b>A</b>); in normal-weight controls, morbidly obese women (MO) without non-alcoholic fatty disease (NAFLD) and morbidly obese women (MO) with NAFLD (<b>B</b>); and in morbidly obese women according to the liver pathology (<b>C</b>). NL, morbidly obese women with normal liver; SS, morbidly obese women with simple steatosis; NASH, morbidly obese women with steatohepatitis. Results are shown as mean ± SD. <i>p</i>< 0.05 are considered statistically significant.</p

Serum alpha-ketoglutarate as a biomarker.

<p>(<b>A</b>) Accuracy of alpha-ketoglutarate biomarker in population studied. Represent the performance for discriminating NAFLD, steatosis and NASH from non- diseased patients. The three values of optimum cutting were selected based on obtaining a first cutoff of high sensitivity (>90%), a second cutoff that included the best combination of sensitivity and specificity according to the Youden index and a third, which prioritized specificity (>90%) (<b>B</b>) Evaluation of a multimetabolite model as biomarkers of NAFLD by the receiver operator characteristic (AUROC) curves. AUROC, area under the curve of receiver operating characteristics; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LR+, positive likelihood ratio; LR-, negative likelihood ratio; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NPV, negative prespective value; PPV, positive prespective value.</p

Correlations between the levels of alpha-ketoglutarate and hepatic enzymes and histopathological parameters in the population studied.

<p>Correlations between the levels of alpha-ketoglutarate and hepatic enzymes and histopathological parameters in the population studied.</p

Anthropometric and metabolic variables of study cohort classified according the BMI and histopathological characteristics.

<p>Anthropometric and metabolic variables of study cohort classified according the BMI and histopathological characteristics.</p