Increased Hepatic ATG7 mRNA and ATG7 Protein Expression in Nonalcoholic Steatohepatitis Associated with Obesity.

The autophagy gene ATG7 has been shown to be essential for the induction of autophagy, a process that used to be suppressed in nonalcoholic fatty liver disease (NAFLD). However, the specific role of ATG7 in NAFLD remains unclear. The aim of this study was to analyze hepatic ATG7 mRNA and ATG7 protein expression regarding obesity-associated NAFLD. Patients included women classified into normal weight (NW, n = 6) and morbid obesity (MO, n = 72). The second group was subclassified into normal liver (NL, n = 11), simple steatosis (SS, n= 29), and nonalcoholic steatohepatitis (NASH, n = 32). mRNA expression was analyzed by RT-qPCR and protein expression was evaluated by Western blotting. Our results showed that NASH patients presented higher ATG7 mRNA and ATG7 protein levels. ATG7 mRNA expression was increased in NASH compared with SS, while ATG7 protein abundance was enhanced in NASH compared with NL. ATG7 mRNA correlated negatively with the expression of some hepatic lipid metabolism-related genes and positively with endocannabinoid receptors, adiponectin hepatic expression, and omentin levels. These results suggest that ATG7-mediated autophagy may play an important role in the pathogenesis of NAFLD, especially in NASH, perhaps playing a possible protective role. However, this is a preliminary study that needs to be further studied.

The Role of Olfactomedin 2 in the Adipose Tissue-Liver Axis and Its Implication in Obesity-Associated Nonalcoholic Fatty Liver Disease.

This study's objective was to assess the involvement of olfactomedin 2 (OLFM2), a secreted glycoprotein related to lipid metabolism regulation, in nonalcoholic fatty liver disease (NAFLD) mediated by the adipose-tissue-liver axis. OLFM2 mRNA expression was analyzed in subcutaneous (SAT) and visceral (VAT) adipose tissue by RT-qPCR. The cohort included women with normal weight (n = 16) or morbid obesity (MO, n = 60) who were subclassified into normal liver (n = 20), simple steatosis (n = 21), and nonalcoholic steatohepatitis (NASH, n = 19) groups. The results showed that OLFM2 expression in SAT was enhanced in MO individuals and in the presence of NAFLD. Specifically, OLFM2 expression in SAT was increased in mild and moderate degrees of steatosis in comparison to the absence of it. Moreover, OLFM2 expression in SAT was negatively correlated with interleukin-6 levels. On the other hand, OLFM2 expression in VAT decreased in the presence of NASH and exhibited a positive correlation with adiponectin levels. In conclusion, OLFM2 in SAT seems to be implicated in hepatic lipid accumulation. Additionally, since we previously suggested the possible implication of hepatic OLFM2 in NAFLD progression, now we propose a possible interaction between the liver and SAT, reinforcing the potential implication of this tissue in NAFLD development.

New Insights of OLFM2 and OLFM4 in Gut-Liver Axis and Their Potential Involvement in Nonalcoholic Fatty Liver Disease.

Olfactomedins (OLFMs) are a family of glycoproteins that play a relevant role in embryonic development and in some pathological processes. Although OLFM2 is involved in the regulation of the energy metabolism and OLFM4 is an important player in inflammation, innate immunity and cancer, the role of OLFMs in NAFLD-related intestinal dysbiosis remains unknown. In this study, we analysed the hepatic mRNA expression of OLFM2 and the jejunal expression of OLFM4 in a well-established cohort of women with morbid obesity (MO), classified according to their hepatic histology into normal liver (n = 27), simple steatosis (n = 26) and nonalcoholic steatohepatitis (NASH, n = 16). Our results showed that OLFM2 hepatic mRNA was higher in NASH, in advanced degrees of steatosis and in the presence of lobular inflammation. Additionally, we obtained positive correlations between hepatic OLFM2 and glucose, cholesterol, trimethylamine N-oxide and deoxycholic acid levels and hepatic fatty acid synthase, and negative associations with weight and jejunal Toll-like receptors (TLR4) and TLR5 expression. Regarding jejunal OLFM4, we observed positive correlations with circulating interleukin (IL)-8, IL-10, IL-17 and jejunal TLR9. In conclusion, OLFM2 in the liver seems to play a relevant role in NAFLD progression, while OLFM4 in the jejunum could be involved in gut dysbiosis-related inflammatory events.

Increased Secreted Frizzled-Related Protein 5 mRNA Expression in the Adipose Tissue of Women with Nonalcoholic Fatty Liver Disease Associated with Obesity.

Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipocytokine secreted by adipocytes that seems to be linked with nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the role of the SFRP5-wingless-MMTV integration site family member 5a (WNT5A) pathway, closely related to adipogenesis, in subcutaneous (SAT) and visceral adipose tissues (VAT) and its relationship with obesity-related NAFLD. Our cohort was composed of 60 women with morbid obesity (MO), who underwent hypocaloric diet, subclassified according to their hepatic histopathology and 15 women with normal weight. We observed increased SFRP5 mRNA expression in VAT and lower WNT5A expression in SAT in MO compared to normal weight. We found elevated SFRP5 expression in nonalcoholic steatohepatitis (NASH) in SAT and in mild simple steatosis (SS) and NASH in VAT. We observed higher WNT5A expression in SS compared to normal liver in SAT, and a peak of WNT5A expression in mild SS. To conclude, we reported increased SFRP5 mRNA expression in SAT and VAT of NAFLD-related to obesity subjects, suggesting an implication of the SFRP5-WNT5A pathway in NAFLD pathogenesis, probably due to the adipose tissue-liver axis. Since the mechanisms by which this potential interaction takes place remain elusive, more research in this field is needed.

Laparoscopic Sleeve Gastrectomy in Patients with Severe Obesity Restores Adaptive Responses Leading to Nonalcoholic Steatohepatitis.

The surgically induced remission of liver disease represents a model to investigate the signalling processes that trigger the development of nonalcoholic steatohepatitis with the aim of identifying novel therapeutic targets. We recruited patients with severe obesity with or without nonalcoholic steatohepatitis and obtained liver and plasma samples before and after laparoscopic sleeve gastrectomy for immunoblotting, immunocytochemical, metabolomic, transcriptomic and epigenetic analyses. Functional studies were performed in HepG2 cells and primary hepatocytes. Surgery was associated with a decrease in the inflammatory response and revealed the role of mitogen-activated protein kinases. Nonalcoholic steatohepatitis was associated with an increased glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy and affected methylation-related epigenomic remodelling enzymes. Hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. Our results suggest that the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation play a crucial role in the inefficient adaptive responses leading to steatohepatitis in obesity.

Metabolic adaptations in severe obesity: Insights from circulating oxylipins before and after weight loss.

BACKGROUND: The relationship between lipid mediators and severe obesity remains unclear. Our study investigates the impact of severe obesity on plasma concentrations of oxylipins and fatty acids and explores the consequences of weight loss. METHODS: In the clinical trial identifier NCT05554224 study, 116 patients with severe obesity and 63 overweight/obese healthy controls matched for age and sex (≈2:1) provided plasma. To assess the effect of surgically induced weight loss, we requested paired plasma samples from 44 patients undergoing laparoscopic sleeve gastrectomy one year after the procedure. Oxylipins were measured using ultra-high-pressure liquid chromatography coupled to a triple quadrupole mass spectrometer via semi-targeted lipidomics. Cytokines and markers of interorgan crosstalk were measured using enzyme-linked immunosorbent assays. RESULTS: We observed significantly elevated levels of circulating fatty acids and oxylipins in patients with severe obesity compared to their metabolically healthier overweight/obese counterparts. Our findings indicated that sex and liver disease were not confounding factors, but we observed weak correlations in plasma with circulating adipokines, suggesting the influence of adipose tissue. Importantly, while weight loss restored the balance in circulating fatty acids, it did not fully normalize the oxylipin profile. Before surgery, oxylipins derived from lipoxygenase activity, such as 12-HETE, 11-HDoHE, 14-HDoHE, and 12-HEPE, were predominant. However, one year following laparoscopic sleeve gastrectomy, we observed a complex shift in the oxylipin profile, favoring species from the cyclooxygenase pathway, particularly proinflammatory prostanoids like TXB2, PGE2, PGD2, and 12-HHTrE. This transformation appears to be linked to a reduction in adiposity, underscoring the role of lipid turnover in the development of metabolic disorders associated with severe obesity. CONCLUSIONS: Despite the reduction in fatty acid levels associated with weight loss, the oxylipin profile shifts towards a predominance of more proinflammatory species. These observations underscore the significance of seeking mechanistic approaches to address severe obesity and emphasize the importance of closely monitoring the metabolic adaptations after weight loss.

Serum Arylesterase, Paraoxonase, and Lactonase Activities and Paraoxonase-1 Concentrations in Morbidly Obese Patients and Their Relationship with Non-Alcoholic Steatohepatitis.

Paraoxonase-1 (PON1) is an antioxidant enzyme associated with high-density lipoproteins (HDL). Reduced serum PON1 activity is found in diseases marked by oxidative stress and inflammation, but its role in obesity remains unclear. This study investigated PON1 activities and concentrations in morbidly obese individuals and explored the impacts of the genetic polymorphism PON1 rs662 and non-alcoholic fatty liver disease on enzymatic properties. We recruited 1349 morbidly obese patients undergoing bariatric surgery and 823 non-obese volunteers. PON1-related variables, including arylesterase, paraoxonase, and lactonase activities and PON1 concentrations, were examined. Our results showed that morbidly obese individuals exhibited higher PON1 concentrations but lower enzymatic activities than non-obese individuals. We observed inverse associations of arylesterase and paraoxonase activities with waist circumference (rho = -0.24, p < 0.001, and rho = -0.30, p < 0.001, respectively) and body mass index (rho = -0.15, p = 0.001, and rho = -0.23, p < 0.001), as well as direct associations of arylesterase, paraoxonase, and lactonase activities with HDL cholesterol (rho = 0.11, p = 0.005, rho = 0.20, p < 0.001, and rho = 0.20, p < 0.001). No significant differences were observed regarding metabolic syndrome, type 2 diabetes mellitus, hypertension, dyslipidemia, rs662 polymorphism allele frequencies, or the diagnosis of non-alcoholic steatohepatitis. Nevertheless, correlations were found between certain PON1-related variables, steatosis, and ballooning. In conclusion, changes in PON1-related variables in morbidly obese patients are dependent on the disease itself and HDL levels. The relationships between these variables and specific liver histological changes raise intriguing questions for consideration in future studies.

Deregulated Serotonin Pathway in Women with Morbid Obesity and NAFLD.

Non-alcoholic fatty liver disease (NAFLD) extends from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH). Peripheral serotonin (5-HT) has become as an important regulator of different metabolic pathways. 5-HT has been related to obesity and lipid accumulation in the liver. The objective of this study was to assess the relationship between the 5-HT signaling pathway and the degree of NAFLD, as well as to investigate whether peripheral 5-HT levels are related to the hepatic and jejunal mRNA abundance of serotonin receptors (HTR) in a cohort of women with morbid obesity (MO) and NAFLD. ELISA was used to quantify the serum 5-HT from normal-weight subjects (n = 26) and patients with MO (n = 58). We used RTq-PCR analysis to evaluate the relative expression of HTR in women with MO with normal liver (n = 22), SS (n = 21), and NASH (n = 15). The 5-HT was diminished in women with MO under a hypocaloric diet, regardless of the presence of NAFLD. Additionally, we report a negative correlation of 5-HT levels with metabolic syndrome criteria, suggesting that serotonin may have a protective role in obesity. Additionally, the hepatic expression of HTR2A and HTR2B were decreased in women with MO and NAFLD, but no significant differences in the HTR jejunal expression according to the presence of NAFLD were found.

Laparoscopic sleeve gastrectomy reverses non-alcoholic fatty liver disease modulating oxidative stress and inflammation.

BACKGROUND & AIMS: Hepatic alterations, such as in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are frequently associated with obesity. To investigate the molecular mechanisms of these alterations and to identify molecules that could be used as potential therapeutic targets, we investigated the modulation of hepatic indices of oxidative stress and inflammation in obese patients undergoing laparoscopic sleeve gastrectomy (LSG). METHODS: Patients (n = 436) attending our obesity clinic underwent LSG for weight loss. We obtained a diagnostic intraoperative liver biopsy, and a sub-cohort (n = 120) agreed to a 1-year follow-up that included donation of blood samples and additional liver biopsies. Selected key molecules in blood and liver tissue were used to investigate the hepatic alterations in obesity, and their response to LSG. RESULTS: One year post-surgery, the prevalence of diabetes, dyslipidemia and hypertension decreased significantly. LSG improved liver histology features in all patients. Improvement was greater in severe cases of NAFLD including those with steatohepatitis, bridging fibrosis or cirrhosis. Significant pre-surgery differences in plasma, and liver markers of oxidative stress and inflammation (including chemokine C-C motif ligand 2, paraoxonase-1, galectin-3, and sonic hedgehog) were observed between patients with, and those without, NASH; post-surgery indicated consistent improvements in these parameters. CONCLUSION: Our study shows that the histology and liver function of patients with morbid obesity are significantly improved after LSG via mechanisms that involve the reduction of oxidative stress and inflammatory processes. These data encourage the use of LSG as a therapeutic option to improve, or resolve, NAFLD.

Clinical and adipocytokine changes after bariatric surgery in morbidly obese women.

OBJECTIVE: Recent studies report the effect of bariatric surgery on glycaemia control and prevention of type-2-diabetes in obese patients. This study is about the pathophysiological mechanisms associated to these changes. DESIGN AND METHODS: Circulating levels of receptors of tumor necrosis factor (TNF-RI, TNF-RII), visfatin, high molecular weight (HMW) adiponectin, and C reactive protein (CRP) in 30 morbidly obese women (body mass index, BMI>40 kg/m(2) ) and 60 normal-weight controls (BMI>25 kg/m(2) ) were analyzed. Morbidly obese were studied at three time-points: before surgery (baseline), and 6 and 12 months after. RESULTS: After surgery, the levels of TNF-RI, TNF-RII, visfatin, and CRP were significantly lower than its baseline levels, whereas HMW adiponectin was higher. Fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA2-IR) levels were markedly lower postoperatively. High density lipoproteins (HDL) moderately increased, and triglyceride levels had sharply decreased. The study of the predictive value of variables indicated that preoperative levels of TNF-RI and visfatin correlated positively with levels of glucose, insulin, glycosylated hemoglobin A1c, and HOMA2-IR postoperatively, whereas adiponectin levels correlated negatively. Baseline CRP levels negatively linked to HDL and TNF-RII positively to triglyceride. CONCLUSIONS: The preoperative profile with high levels of proinflammatory adipocytokines is linked to smaller improvements in glucose homeostasis and lipid factors. The use of a range of biomarkers may predict the level of metabolic changes following bariatric surgery.

La escuela en tiempos de guerra: una mirada a la educación desde la crisis y la violencia / School in times of war: a look to education from crisis and violence

Diagnostica las deficiencias de la escuela peruana acrecentadas por la violencia y propone al magisterio nacional y a la sociedad civil soluciones democráticas, participativas, opuestas al autoritarismo ideológico, al centralismo esterilizante y a todo intento a vender adoctrinamiento por educación. Propone recobrar no sólo el espacio educativo sino usarlo para el desarrollo humano