C. Saponaro

The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis.

Excessive accumulation of lipids can lead to lipotoxicity, cell dysfunction and alteration in metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. This is now a recognized risk factor for the development of metabolic disorders, such as obesity, diabetes, fatty liver disease (NAFLD), cardiovascular diseases (CVD) and hepatocellular carcinoma (HCC). The causes for lipotoxicity are not only a high fat diet but also excessive lipolysis, adipogenesis and adipose tissue insulin resistance. The aims of this review are to investigate the subtle balances that underlie lipolytic, lipogenic and oxidative pathways, to evaluate critical points and the complexities of these processes and to better understand which are the metabolic derangements resulting from their imbalance, such as type 2 diabetes and non alcoholic fatty liver disease.

Not all fats are created equal: adipose vs. ectopic fat, implication in cardiometabolic diseases.

Abstract Adipose tissue is a recognized endocrine organ that acts not only as a fuel storage but also is able to secrete adipokines that can modulate inflammation. Most of the fat is composed of white adipocytes (WAT), although also brown/beige adipocytes (BAT/BeAT) have been found in humans. BAT is located close to the neck but also among WAT in the epicardial fat and perivascular fat. Adipocyte hypertrophy and infiltration of macrophages impair adipose tissue metabolism determining “adiposopathy” (i.e., sick fat) and increasing the risk to develop metabolic and cardiovascular diseases. The purpose of this review was to search and discuss the available literature on the impact of different types of fat and fat distribution on cardiometabolic risk. Visceral fat, but also ectopic fat, either in liver, muscle and heart, can increase the risk to develop insulin resistance, type 2 diabetes and cardiovascular diseases. Results recently published showed that BAT could have an impact on cardiometabolic risk, not only because it is implicated in energy metabolism but also because it can modulate glucose and lipid metabolism. Therapeutical interventions that can increase energy expenditure, successfully change fat distribution and reduce ectopic fat, also through BAT activation, were discussed.

Peripheral insulin resistance predicts liver damage in nondiabetic subjects with nonalcoholic fatty liver disease

Surrogate indexes of insulin resistance and insulin sensitivity are widely used in nonalcoholic fatty liver disease (NAFLD), although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with the NAFLD fibrosis score. Surrogate indexes were validated by the tracer technique (6,6‐D2‐glucose and U‐13C‐glucose) in the basal state and during an oral glucose tolerance test. The best‐performing indexes were used in an independent cohort of 145 nondiabetic NAFLD subjects to identify liver damage (fibrosis and nonalcoholic steatohepatitis). In the validation NAFLD cohort, homeostasis model assessment of insulin resistance, insulin to glucose ratio, and insulin sensitivity index Stumvoll had the best association with hepatic insulin resistance, while peripheral insulin sensitivity was most significantly related to oral glucose insulin sensitivity index (OGIS), insulin sensitivity index Stumvoll, and metabolic clearance rate estimation without demographic parameters. In the independent cohort, only oral glucose tolerance test‐derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (odds ratio = 0.76, 95% confidence interval 0.61‐0.96, P = 0.0233) and of nonalcoholic steatohepatitis (odds ratio = 0.75, 95% confidence interval 0.63‐0.90, P = 0.0021). Both OGIS and NAFLD fibrosis score identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NAFLD fibrosis score (odds ratio = 0.57, 95% confidence interval 0.45‐0.72, P < 0.001) and was also able to discriminate F2 from F3/F4 (P < 0.003). Conclusion: OGIS is associated with peripheral insulin sensitivity in NAFLD and inversely associated with an increased risk of significant/advanced liver damage in nondiabetic subjects with NAFLD. (Hepatology 2016;63:107–116)

Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD

Non-Alcoholic Fatty Liver Disease (NAFLD) represents the most common form of chronic liver injury and can progress to cirrhosis and hepatocellular carcinoma. A “multi-hit” theory, involving high fat diet and signals from the gut-liver axis, has been hypothesized. The role of the NLRP3-inflammasome, which senses dangerous signals, is controversial. Nlrp3−/− and wild-type mice were fed a Western-lifestyle diet with fructose in drinking water (HFHC) or a chow diet. Nlrp3−/−-HFHC showed higher hepatic expression of PPAR γ2 (that regulates lipid uptake and storage) and triglyceride content, histological score of liver injury and greater adipose tissue inflammation. In Nlrp3−/−-HFHC, dysregulation of gut immune response with impaired antimicrobial peptides expression, increased intestinal permeability and the occurrence of a dysbiotic microbiota led to bacterial translocation, associated with higher hepatic expression of TLR4 (an LPS receptor) and TLR9 (a receptor for double-stranded bacterial DNA). After antibiotic treatment, gram-negative species and bacterial translocation were reduced, and adverse effects restored both in liver and adipose tissue. In conclusion, the combination of a Western-lifestyle diet with innate immune dysfunction leads to NAFLD progression, mediated at least in part by dysbiosis and bacterial translocation, thus identifying new specific targets for NAFLD therapy.

Adipose tissue insulin resistance is associated with macrophage activation in non-diabetic patients with non-alcoholic fatty liver disease

M. Marietti 1, C. Rosso1, M. Gaggini2, C. Saponaro2, K. Kazankov3, E. Buzzigoli 2, H.J. Moller4, G.P. Caviglia1, M.L. Abate1, A. Smedile1, G.M. Saracco5,6, H. Vilstrup3, J. George5,6, H. Gronbaek3, A. Gastaldelli 3, E. Bugianesi1 1 Department of Medical Sciences, University of Torino, Torino, Italy 2 Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy 3 Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark 4 Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark 5 The Storr Liver Centre, University of Sydney and Westmead Hospital, Westmead, Australia 6 Department of Oncology, University of Turin, Turin, Italy

P840 ALTERATION IN LIPID METABOLISM AFTER AN ORAL FAT LOAD IN PATIENTS WITH NAFLD

P840 ALTERATION IN LIPID METABOLISM AFTER AN ORAL FAT LOAD IN PATIENTS WITH NAFLD L. Mezzabotta, E. Vanni, C. Rosso, M. Gaggini, R. Gambino, E. Buzzigoli, C. Saponaro, D. Ciociaro, M.L. Abate, F. Saba, F. Salomone, G.P. Caviglia, S. Carenzi, A. Smedile, M. Rizzetto, M. Cassader, A. Gastaldelli, E. Bugianesi. Medical Sciences, University of Turin, Turin, Cardiometabolic Risk Unit, Institute of Clinical Physiology – CNR, Pisa, U.O.C. of Gastroenterology, Azienda Sanitaria Provinciale di Catania, Catania, Italy E-mail: laviniaemme@hotmail.com

P843 ALTERATION IN GLUCOSE METABOLISM AFTER AN ORAL GLUCOSE LOAD AND RELATIONSHIP WITH LIVER DAMAGE IN PATIENTS WITH NAFLD

P840 ALTERATION IN LIPID METABOLISM AFTER AN ORAL FAT LOAD IN PATIENTS WITH NAFLD L. Mezzabotta, E. Vanni, C. Rosso, M. Gaggini, R. Gambino, E. Buzzigoli, C. Saponaro, D. Ciociaro, M.L. Abate, F. Saba, F. Salomone, G.P. Caviglia, S. Carenzi, A. Smedile, M. Rizzetto, M. Cassader, A. Gastaldelli, E. Bugianesi. Medical Sciences, University of Turin, Turin, Cardiometabolic Risk Unit, Institute of Clinical Physiology – CNR, Pisa, U.O.C. of Gastroenterology, Azienda Sanitaria Provinciale di Catania, Catania, Italy E-mail: laviniaemme@hotmail.com