Eva Pardina

Surgically induced weight loss by gastric bypass improves non alcoholic fatty liver disease in morbid obese patients

AIM To evaluate the effects of surgical weight loss (Roux-en-Y gastric bypass with a modified Fobi-Capella technique) on non alcoholic fatty liver disease in obese patients. METHODS A group of 26 morbidly obese patients aged 45 ± 2 years and with a body mass index > 40 kg/m(2) who underwent open surgical weight loss operations had paired liver biopsies, the first at surgery and the second after 16 ± 3 mo of weight loss. Biopsies were evaluated and compared in a blinded fashion. The presence of metabolic syndrome, anthropometric and biochemical variables were also assessed at baseline and at the time of the second biopsy. RESULTS Percentage of excess weight loss was 72.1% ± 6.6%. There was a reduction in prevalence of metabolic syndrome from 57.7% (15 patients) to 7.7% (2 patients) (P < 0.001). Any significance difference was observed in aspartate aminotransferase or alanine aminotransferase between pre and postsurgery. There were improvements in steatosis (P < 0.001), lobular (P < 0.001) and portal (P < 0.05) inflammation and fibrosis (P < 0.001) at the second biopsy. There were 25 (96.1%) patients with non alcoholic steatohepatitis (NASH) in their index biopsy and only four (15.3%) of the repeat biopsies fulfilled the criteria for NASH. The persistence of fibrosis (F > 1) was present in five patients at second biopsy. Steatosis and fibrosis at surgery were predictors of significant fibrosis postsurgery. CONCLUSION Restrictive mildly malabsorptive surgery provides significant weight loss, resolution of metabolic syndrome and associated abnormal liver histological features in most obese patients.

Alterations in the Common Pathway of Coagulation During Weight Loss Induced by Gastric Bypass in Severely Obese Patients

The objective of this study was to establish the relationship between the plasminogen activator inhibitor‐1 (PAI‐1), antithrombin‐III (ATIII), fibrinogen, and white blood cell (WBC) levels in severely obese patients. We analyzed various plasma parameters implicated in the intrinsic and extrinsic coagulation pathway from 34 severely obese patients before and 1, 6, and 12 months after gastric bypass. In obese people, ATIII, fibrinogen, and WBC levels were in the upper limit of the normal range, and all were higher and significantly different from nonobese people. After bariatric surgery, the ATIII level continued to be high during the first month and increased until 12 months, while fibrinogen decreased only at that time. PAI‐1 plasma protein and PAI‐1 mRNA levels in liver and adipose tissue show similar profiles and had a strong positive correlation (r = 0.576, P = 0.0003 in liver; r = 0.433, P = 0.0004 in adipose tissue). They were higher in obese patients compared with nonobese control, but tended to recover normal values 1 month after surgery. Thus, the liver and adipose tissue could be an important source of PAI‐1 protein in plasma. Gastric bypass surgery leads to a normalization of the hematological profile and a decrease in PAI‐1 levels, which entails a decrease of risk for thromboembolism in severely obese.

Expression, localization, and regulation of the neuregulin receptor ErbB3 in mouse heart

Neuregulins (NRG) belong to the EGF family of growth factors, which are ligands of the ErbB receptors. Their expression in the adult heart is essential, especially when the heart is submitted to cardiotoxic stress such as that produced by anthracyclines. It is considered that ErbB4 is the only NRG receptor expressed by the adult heart. Upon binding, ErbB4 may dimerize with ErbB2 to generate signals inside cells. However, here we show the presence of ErbB3 in the mouse heart from birth to adulthood by Western blotting and real‐time RT‐PCR. The expression level of ErbB3 mRNA was lower than that of ErbB2 or ErbB4, but was more stable throughout postnatal development. In isolated heart myocytes, ErbB3 localized to the Z‐lines similarly to ErbB1. Perfusion of isolated hearts with NRG‐1β induced phosphorylation of ErbB3, as well as ErbB2 and ErbB4. In adult mice, both ErbB2 and ErbB3, but not ErbB1 or ErbB4, were rapidly down‐regulated upon the induction of heart hypertrophy. In conclusion, our results demonstrate that ErbB3, in addition to ErbB4, is a receptor for neuregulin‐1β in the adult mouse heart. J. Cell. Physiol. 226: 450–455, 2011.

Bariatric surgery in morbidly obese patients improves the atherogenic qualitative properties of the plasma lipoproteins

OBJECTIVE The purpose of this study was to evaluate the effect of weight loss induced in morbidly obese subjects by Roux-en-Y gastric bypass bariatric surgery on the atherogenic features of their plasma lipoproteins. METHODS Twenty-one morbidly obese subjects undergoing bariatric surgery were followed up for up to 1 year after surgery. Plasma and lipoproteins were assayed for chemical composition and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity. Lipoprotein size was assessed by non-denaturing polyacrylamide gradient gel electrophoresis, and oxidised LDL by ELISA. Liver samples were assayed for mRNA abundance of oxidative markers. RESULTS Lipid profile analysis revealed a reduction in the plasma concentrations of cholesterol and triglycerides, which were mainly associated with a significant reduction in the plasma concentration of circulating apoB-containing lipoproteins rather than with changes in their relative chemical composition. All patients displayed a pattern A phenotype of LDL subfractions and a relative increase in the antiatherogenic plasma HDL-2 subfraction (>2-fold; P < 0.001). The switch towards predominantly larger HDL particles was due to an increase in their relative cholesteryl ester content. Excess weight loss also led to a significant decrease in the plasma concentration of oxidised LDL (∼-25%; P < 0.01) and in the total Lp-PLA2 activity. Interestingly, the decrease in plasma Lp-PLA2 was mainly attributed to a decrease in the apoB-containing lipoprotein-bound Lp-PLA2. CONCLUSION Our data indicate that the weight loss induced by bariatric surgery ameliorates the atherogenicity of plasma lipoproteins by reducing the apoB-containing Lp-PLA2 activity and oxidised LDL, as well as increasing the HDL-2 subfraction.

Soluble CD40 ligand in morbidly obese patients: effect of body mass index on recovery to normal levels after gastric bypass surgery.

IMPORTANCE In recent years, the CD40/CD40L system has been implicated in the pathophysiology of severe chronic inflammatory diseases. Recently, obesity has been described as a low chronic inflammatory disease, so this system could also be involved in the inflammatory process. OBJECTIVE To study soluble CD40 ligand (sCD40L) and other factors implicated in coagulation (plasminogen activator inhibitor 1, antithrombin III, and fibrinogen) and inflammation (C-reactive protein) in patients with morbid obesity and different body mass indexes (BMIs) (calculated as weight in kilograms divided by height in meters squared), before and after weight loss induced by bariatric surgery. DESIGN Plasma samples were obtained before and after a bariatric surgery intervention. Several inflammatory markers were then studied (sCD40L, plasminogen activator inhibitor 1, antithrombin III, and C-reactive protein). The values obtained were compared with a control group of nonobese persons. PARTICIPANTS Thirty-four morbidly obese patients undergoing gastric bypass surgery and 22 normal-weight controls matched for age and sex. INTERVENTIONS A Roux-en-Y gastric bypass was performed in morbidly obese patients. MAIN OUTCOME MEASURES Levels of sCD40L, plasminogen activator inhibitor 1, antithrombin III, fibrinogen, and C-reactive protein 12 months after bariatric surgery. RESULTS Obese men showed a tendency for decreased plasma sCD40L levels 1 year after surgery (mean [SEM], 246.5 [70.4] pg/mL before vs 82.2 [23.2] pg/mL after surgery; P < .05), whereas there were not any significant changes in obese women (285.9 [67.5] pg/mL before vs 287.0 [56.9] pg/mL after surgery). Levels of the other markers studied decreased significantly with weight loss in both sexes. However, all other studied markers tend to have higher concentrations in patients with higher BMIs, except for sCD40L, which tended to have lower concentrations in patients with BMIs higher than 55. The decreases with weight loss were lower with higher BMIs for all measurements, except for antithrombin III. CONCLUSIONS AND RELEVANCE Increased BMI, but not sex, influences recovery to normal levels for the markers studied, possibly indicating a worse prognosis.

Morbidly “Healthy” Obese Are Not Metabolically Healthy but Less Metabolically Imbalanced Than Those with Type 2 Diabetes or Dyslipidemia

BackgroundWe have investigated the differences between metabolically “healthy” morbidly obese patients and those with comorbidities.Materials and MethodsThirty-two morbidly obese patients were divided by the absence (“healthy”: DM−DL−) or presence of comorbidities (dyslipidemic: DM−DL+, or dyslipidemic and with type 2 diabetes: DM+DL+). We have studied various plasma parameters and gene expression adipose tissue, before and after gastric bypass.ResultsThe group DM+DL+ tends to have lower values than the other two groups for anthropometric parameters. Regarding the satiety parameters, only leptin (p = 0.0024) showed a significant increase with comorbidities. Lipid parameters showed significant differences among groups, except for phospholipids and NEFA. For insulin resistance parameters, only glucose (p < 0.0001) was higher in DM+DL+ patients, but not insulin or homeostasis model assessment of insulin resistance (HOMA-IR). The gene expression of adiponectin, insulin receptor (INSR) and glucose receptor-4 (GLUT4), in the subcutaneous fat, decreased in all groups vs. a non-obese control. Interleukin-6 (IL6) and the inhibitor of plasminogen activator type 1 (PAI-1) genes decreased only in DM−DL+ and DM+DL+, but not in “healthy” patients. Leptin increased in all groups vs. the non-obese control. The visceral fat from DM+DL+ patients showed a sharp decrease in adiponectin, GLUT4, IL6 and PAI-1. All parameters mentioned above improved very significantly by surgery, independent of the occurrence of comorbidities.ConclusionsThe morbidly obese “healthy” individual is not really metabolically healthy, but morbidly obese individuals with diabetes and dyslipidemia are more metabolically imbalanced.

Decreased lipases and fatty acid and glycerol transporter could explain reduced fat in diabetic morbidly obese.

The possible differences were investigated in 32 morbidly obese patients depending on whether they were “healthy” or had dyslipidemia and/or type 2 diabetes.

LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity

&NA; Diabesity and fatty liver have been associated with low levels of high‐density lipoprotein cholesterol, and thus could impair macrophage‐specific reverse cholesterol transport (m‐RCT). Liver X receptor (LXR) plays a critical role in m‐RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m‐RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage‐derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m‐RCT by elevating the liver and small intestine expressions of Abcg5/g8.

Seasonal variation in plasma lipids and lipases in young healthy humans

ABSTRACT Although intermediate metabolism is known to follow circadian rhythms, little information is available on the variation in lipase activities (lipoprotein and hepatic lipase, LPL and HL, respectively) and lipids throughout the year. In a cross-sectional study, we collected and analysed blood from 245 healthy students (110 men and 135 women) between 18 and 25 years old from the University of Barcelona throughout the annual campaign (March, May, October and December) of the blood bank. All subjects gave their written informed consent to participate. All blood samples were taken after breakfast at 8:00 and 11:00 am. Plasma glucose, total plasma protein, triacylglycerides (TAG), free fatty acids (FFA), free cholesterol and esterified cholesterol (FC and TC, respectively), cholesterol in low-density lipoproteins (cLDL), cholesterol in high-density lipoproteins (cHDL), phospholipids (PL) and lipase activities (LPL and HL) were determined. Cosinor analysis was used to evaluate the presence (significance of fit cosine curve to data and variance explained by rhythm) and characteristics of possible 12-month rhythms (acrophase, MESOR and amplitude). Statistically significant seasonal rhythms were detected for all the variables studied except proteins, with most of them peaking in the winter season. The lowest value for cLDL and the HL occurs in summer, while for cHDL and the LPL it is in winter. These findings demonstrate for the first time that in physiological conditions, plasma LPL and HL activities and lipids follow seasonal rhythms. The metabolic significance of this pattern is discussed.

Diabetic and dyslipidaemic morbidly obese exhibit more liver alterations compared with healthy morbidly obese.

Background & aims To study the origin of fat excess in the livers of morbidly obese (MO) individuals, we analysed lipids and lipases in both plasma and liver and genes involved in lipid transport, or related with, in that organ. Methods Thirty-two MO patients were grouped according to the absence (healthy: DM − DL −) or presence of comorbidities (dyslipidemic: DM − DL +; or dyslipidemic with type 2 diabetes: DM + DL +) before and one year after gastric bypass. Results The livers of healthy, DL and DM patients contained more lipids (9.8, 9.5 and 13.7 times, respectively) than those of control subjects. The genes implicated in liver lipid uptake, including HL, LPL, VLDLr, and FAT/CD36, showed increased expression compared with the controls. The expression of genes involved in lipid-related processes outside of the liver, such as apoB, PPARα and PGC1α, CYP7a1 and HMGCR, was reduced in these patients compared with the controls. PAI1 and TNFα gene expression in the diabetic livers was increased compared with the other obese groups and control group. Increased steatosis and fibrosis were also noted in the MO individuals. Conclusions Hepatic lipid parameters in MO patients change based on their comorbidities. The gene expression and lipid levels after bariatric surgery were less prominent in the diabetic patients. Lipid receptor overexpression could enable the liver to capture circulating lipids, thus favouring the steatosis typically observed in diabetic and dyslipidaemic MO individuals.