Insulin-Stimulated Degradation of Apolipoprotein B100: Roles of Class II Phosphatidylinositol-3-Kinase and Autophagy

Both in humans and animal models, an acute increase in plasma insulin levels, typically following meals, leads to transient depression of hepatic secretion of very low density lipoproteins (VLDL). One contributing mechanism for the decrease in VLDL secretion is enhanced degradation of apolipoprotein B100 (apoB100), which is required for VLDL formation. Unlike the degradation of nascent apoB100, which occurs in the endoplasmic reticulum (ER), insulin-stimulated apoB100 degradation occurs post-ER and is inhibited by pan-phosphatidylinositol (PI)3-kinase inhibitors. It is unclear, however, which of the three classes of PI3-kinases is required for insulin-stimulated apoB100 degradation, as well as the proteolytic machinery underlying this response. Class III PI3-kinase is not activated by insulin, but the other two classes are. By using a class I-specific inhibitor and siRNA to the major class II isoform in liver, we now show that it is class II PI3-kinase that is required for insulin-stimulated apoB100 degradation in primary mouse hepatocytes. Because the insulin-stimulated process resembles other examples of apoB100 post-ER proteolysis mediated by autophagy, we hypothesized that the effects of insulin in autophagy-deficient mouse primary hepatocytes would be attenuated. Indeed, apoB100 degradation in response to insulin was significantly impaired in two types of autophagy-deficient hepatocytes. Together, our data demonstrate that insulin-stimulated apoB100 degradation in the liver requires both class II PI3-kinase activity and autophagy. © 2013 Andreo et al

HIV/HCV Co-infection: Pathogenesis, Clinical Complications, Treatment, and New Therapeutic Technologies

World-wide, hepatitis C virus (HCV) accounts for approximately 130 million chronic infections, with an overall 3% prevalence. Four to 5 million persons are co-infected with HIV. It is well established that HIV has a negative impact on the natural history of HCV, including a higher rate of viral persistence, increased viral load, and more rapid progression to fibrosis, end-stage liver disease, and death. Whether HCV has a negative impact on HIV disease progression continues to be debated. However, following the introduction of effective combination antiretroviral therapy, the survival of coinfected individuals has significantly improved and HCV-associated diseases have emerged as the most important co-morbidities. In this review, we summarize the newest studies regarding the pathogenesis of HIV/HCV coinfection, including effects of coinfection on HIV disease progression, HCV-associated liver disease, the immune system, kidney and cardiovascular disease, and neurologic status; and effectiveness of current anti-HIV and HCV therapies and proposed new treatment strategies

ACIDFORM inactivates herpes simplex virus and prevents genital herpes in a mouse model: Optimal candidate for microbicide combinations

The acidic vaginal milieu is presumed to inactivate pathogens but is neutralized by semen. This notion fostered the development of acid-buffering products, such as ACIDFORM (developed by Program for Topical Prevention of Conception and Disease, Rush University, and licensed by Instead), as microbicides. However, the extent and mechanism of protective activity provided by buffering gels is not known. Exposure of herpes simplex virus (HSV) to pH 4.5 or lower irreversibly inactivated HSV and reduced HSV yields by at least 90%; exposure to pH 5.0 had little or no effect. Pretreatment of HSV-2 with pH 3.5-4.5 triggered proteolysis, disrupting the HSV particle and resulting in a reduction in binding and invasion. ACIDFORM protected 21 (81%) of 26 mice from genital herpes, compared with 3 (12%) of 25 mice who received a placebo gel. ACIDFORM retained significant activity if mice were challenged with HSV delivered in seminal fluid. These findings suggest that ACIDFORM offers considerable protection against HSV and may be an optimal candidate for developing combination microbicides.Fil: Tuyama, Ana C. G.. Mount Sinai School of Medicine; Estados UnidosFil: Cheshenko, Natalia. Mount Sinai School of Medicine; Estados UnidosFil: Carlucci, Maria Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Mount Sinai School of Medicine; Estados UnidosFil: Li, Jin Hua. Mount Sinai School of Medicine; Estados UnidosFil: Goldberg, Cindy L.. Mount Sinai School of Medicine; Estados UnidosFil: Waller, Donald P.. University of Illinois; Estados UnidosFil: Anderson, Robert A.. Rush University; ArgentinaFil: Profy, Albert T.. Indevus Pharmaceuticals; Estados UnidosFil: Klotman, Mary E.. Mount Sinai School of Medicine; Estados UnidosFil: Keller, Maria J.. Mount Sinai School of Medicine; Estados UnidosFil: Herold, Betsy C.. Mount Sinai School of Medicine; Estados Unido