Liane Rabinowich

Sortilin deficiency improves the metabolic phenotype and reduces hepatic steatosis of mice subjected to diet-induced obesity

BACKGROUND & AIMS Sortilin traffics newly synthesized molecules from the trans-Golgi apparatus along secretory pathways to endosomes, lysosomes or to the cell surface. Sortilin trafficking of acid sphingomyelinase (aSMase) may regulate ceramide levels, a major modulator of insulin signalling. We therefore tested whether sortilin deficiency reduces hepatic and adipose tissue aSMase activity, improving insulin sensitivity in diet-induced obesity (DIO). METHODS DIO in C57BL/6 (WT) and sortilin(-/-) mice was induced by high-fat diet feeding for 10 weeks. RESULTS Sortilin(-/-) mice gained less body weight and less visceral fat, despite similar food intake compared to WT type mice and had enhanced glucose uptake in insulin tolerance tests, which was further corroborated by enhanced hepatic pAkt expression. Sortilin deficiency led to attenuated hepatic steatosis, reduced expression of genes involved in lipogenesis, ceramide synthesis and inflammatory cytokine production and reduced activity of ceramide synthase 5/6 (CerS5/6). Sortilin(-/-) mice had reduced hepatic aSMase activity under both steady-state and DIO. Likewise, sortilin(-/-) hepatocytes displayed hypersensitivity to insulin, due to enhanced insulin receptor downstream signalling. In adipose tissue, sortilin(-/-) mice exhibited lower expression of inflammatory cytokines and lower expression and activity of CerS5/6. As in liver, adipose tissue displayed increased insulin signalling, accompanied by attenuated aSMase activity. CONCLUSIONS Sortilin deficiency induces a beneficial metabolic phenotype in liver and adipose tissue upon DIO, mediated in part by reduced aSMase activity.

Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI). The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrial β-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis.

The association between the serum levels of uric acid and alanine aminotransferase in a population-based cohort

Elevated serum uric acid levels reflect and also cause both oxidative stress and insulin resistance and are frequently observed in patients with the metabolic syndrome. A strong association exists between the metabolic syndrome and non‐alcoholic fatty liver disease (NAFLD). Therefore, we aimed to test the association between uric acid and elevated alanine aminotransferase (ALT), as a surrogate for NAFLD, using real‐world data.

Adherence to statins is associated with reduced incidence of idiopathic venous thromboembolism: real-life data from a large healthcare maintenance organisation

Objective Previous reports on the association between statin use and venous thromboembolism (VTE) did not examine patient adherence to medications, thus their applicability in a real life setting is questionable. Our objective was to investigate the association between the use of statins and incidence of first ever idiopathic VTE. Design A retrospective cohort study. Settings A large healthcare maintenance organisation. Patients Included were statin initiators aged 30 years or older since 2003 who did not have a statin prescription for at least 4 years before that and had at least 18 months follow-up. Excluded were patients with known risk factors for VTE. End of follow-up was defined as the first of the following: leaving Maccabi Healthcare Services, death, VTE or October 27, 2010. Interventions Prescription drug purchase data was analysed in order to evaluate the association between statin use and adherence and between VTE prevention. Main outcome measures VTE diagnosis during follow-up. Results The study population included 127 822 subjects (53 618 females). The follow-up period was comprised of 594 190 patient years, and included 1375 VTE cases and 5-year cumulative incidence rate of 1.15%. Cox regression analysis demonstrated a significantly lower VTE risk of 19% and 22% in the more adherent patient groups, compared to the risk for the lowest adherence group. The simvastatin dose, the most frequently prescribed statin, was negatively associated with the risk of VTE. Conclusions In a real life healthcare maintenance organisation setting, better adherence to statins is associated with a reduced risk of first ever idiopathic VTE events.

Clinical management of acute liver failure: Results of an international multi-center survey

AIM To assess the practice of caring for acute liver failure (ALF) patients in varying geographic locations and medical centers. METHODS Members of the European Acute Liver Failure Consortium completed an 88-item questionnaire detailing management of ALF. Responses from 22 transplantation centers in 11 countries were analyzed, treating between 300 and 500 ALF cases and performing over 100 liver transplants (LT) for ALF annually. The questions pertained to details of the institution and their clinical activity, standards of care, referral and admission, ward- based care versus intensive care unit (ICU) as well as questions regarding liver transplantation - including criteria, limitations, and perceived performance. Clinical data was also collected from 13 centres over a 3 mo period. RESULTS The interval between referral and admission of ALF patients to specialized units was usually less than 24 h and once admitted, treatment was provided by a multidisciplinary team. Principles of care of patients with ALF were similar among centers, particularly in relation to recognition of severity and care of the more critically ill. Centers exhibited similarities in thresholds for ICU admission and management of severe hepatic encephalopathy. Over 80% of centers administered n-acetyl-cysteine to ICU patients for non-paracetamol-related ALF. There was significant divergence in the use of prophylactic antibiotics and anti-fungals, lactulose, nutritional support and imaging investigations in admitted patients and in the monitoring and treatment of intra-cranial pressure (ICP). ICP monitoring was employed in 12 centers, with the most common indications being papilledema and renal failure. Most patients listed for transplantation underwent surgery within an average waiting time of 1-2 d. Over a period of 3 mo clinical data from 85 ALF patients was collected. Overall patient survival at 90-d was 76%. Thirty six percent of patients underwent emergency LT, with a 90% post transplant survival to hospital discharge, 42% survived with medical management alone. CONCLUSION Alongside similarities in principles of care of ALF patients, major areas of divergence were present in key areas of diagnosis, monitoring, treatment and decision to transplant.

P283 SORTILIN DEFICIENCY IMPROVES HEPATIC AND ADIPOSE TISSUE INSULIN RESISTANCE AND INFLAMMATION IN DIET-INDUCED OBESITY

Background and Aims: Sortilin is a trafficking molecule directing newly synthesized molecules from the trans-Golgi network to secretory pathways, endosomes, lysosomes or cell surface. Several of the molecules trafficked by sortilin, such as acidic sphingomyelinase (ASM) and sphingolipid activating proteins (SAPs), regulate the synthesis of ceramide, a major modulator of insulin signaling. We hypothesized that in sortilin mice, reduced hepatic ASM may improve insulin sensitivity and reduce steatosis in a diet-induced obesity (DIO) model. Methods: DIO and insulin resistance were induced by feeding high fat diet for 10 weeks to WT and sortilin mice. Results: Sortilin mice had significantly reduced body weight and visceral fat, despite similar food intake. Sortilin mice had better insulin tolerance test and displayed increased insulin signaling in both liver and adipose tissue as demonstrated by increased Akt phosphorylation. In accordance with the proposed role of sortilin in ASM trafficking, ASM activity in both liver and adipose tissue of sortilin mice was significantly reduced. Sortilin mice had almost no steatosis and a three-fold reduction in total hepatic triglyceride levels compared to WT mice. In addition, expression of proinflammatory cytokines was reduce in both livers and adipose tissue of sortilin. Looking at ceramide synthesis enzymes, we observed a significant reduction in ceramide synthase 6, which synthesizes long chain ceramides, in both liver and adipose tissue of sortilin. Conclusions: Sortilin deficiency induces a beneficial metabolic phenotype in DIO, with respect to both liver and adipose tissue, which may be mediated in part by reduced ASM activity and reduced ceramide levels.

Response to The relationship between serum uric acid levels and NAFLD.

age were quite remarkable. This study brings a new perspective on NAFLD. But it does not provide sufficient data on obesity, insulin resistance, diabetes mellitus, metabolic syndrome, hyperlipidaemia and thyroid function, which are important risk factors for NAFLD. Therefore, we would like to make some important contributions in this regard. It is well known that insulin resistance commonly coexists with NAFLD and it plays a key role in lipid accumulation in the liver. On the other hand, impaired thyroid hormone action, which may cause decreased mitochondrial oxidative capacity and make changes in gene expression (regarding RNA, protein and energy metabolism) in the liver, further leads to the lipid accumulation in the liver (2, 3). It is believed that hyperuricaemia and insulin resistance share some bidirectional causal effects. For example, (a) insulin resistance induces hyperinsulinaemia, which may increase renal urate reaborption by stimulating urate– anion exchange, (b) insulin reduces the uric acid excretion from renal tubular, (c) high levels of uric acid provoke cell proliferation and proinflammatory effect on adipocytes, impair insulin sensitivity and glucose effectiveness of cells for the glucose transport and lead to insulin resistance, which is very important in obesity, type 2 diabetes mellitus and metabolic syndrome, and endothelial dysfunction caused by impaired use of the nitric oxide (4, 5). In conclusion, while evaluating the relationship between NAFLD and SUA level, parameters like anthropometric measurements of obesity, insulin, homoeostasis model assessment: insulin resistance and glucose levels should also be assessed to reveal molecular processes and mechanisms of this relationship. Otherwise, owing to lack of this cause–effect relationship, the strength of the correlation presented in this study is becoming controversial. Acknowledgement