ABSTRACT
Lipid droplets are essential cellular organelles for storage of fatty acids and triglycerides. The hepatitis C virus (HCV) translocates several of its proteins onto their surface and uses them for production of infectious progeny. We recently reported that the lipid droplet-associated α/ß hydrolase domain-containing protein 5 (ABHD5/CGI-58) participates in HCV assembly by mobilizing lipid droplet-associated lipids. However, ABHD5 itself has no lipase activity and it remained unclear how ABHD5 mediates lipolysis critical for HCV assembly. Here, we identify adipose triglyceride lipase (ATGL) as ABHD5 effector and new host factor involved in the hepatic lipid droplet degradation as well as in HCV and lipoprotein morphogenesis. Modulation of ATGL protein expression and lipase activity controlled lipid droplet lipolysis and virus production. ABHD4 is a paralog of ABHD5 unable to activate ATGL or support HCV assembly and lipid droplet lipolysis. Grafting ABHD5 residues critical for activation of ATGL onto ABHD4 restored the interaction between lipase and co-lipase and bestowed the pro-viral and lipolytic functions onto the engineered protein. Congruently, mutation of the predicted ABHD5 protein interface to ATGL ablated ABHD5 functions in lipid droplet lipolysis and HCV assembly. Interestingly, minor alleles of ABHD5 and ATGL associated with neutral lipid storage diseases in human, are also impaired in lipid droplet lipolysis and their pro-viral functions. Collectively, these results show that ABHD5 cooperates with ATGL to mobilize triglycerides for HCV infectious virus production. Moreover, viral manipulation of lipid droplet homeostasis via the ABHD5-ATGL axis, akin to natural genetic variation in these proteins, emerges as a possible mechanism by which chronic HCV infection causes liver steatosis.
Subject(s)
1-Acylglycerol-3-Phosphate O-Acyltransferase/metabolism , Hepacivirus/physiology , Lipase/metabolism , Lipid Droplets/metabolism , Lipolysis , Virus Assembly/physiology , 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics , Cell Line, Tumor , Enzyme Activation , HEK293 Cells , Humans , Lipase/genetics , Lipid Droplets/virology , Triglycerides/genetics , Triglycerides/metabolismABSTRACT
The increased number of adolescents and young adults with unknown or inaccurately given date of birth is a current issue in justice and legal medicine. The objective of this study was to determine the extent to which third molar calcification stages assessed on panoramic X-rays could be useful as additional criteria for forensic age estimation in living individuals, focusing on the legally important ages 17 and 18. In a retrospective multi-center study, the developmental stage of each individual's third molar was analyzed using Demirjian's scale in 2360 cases. Additionally, sex, age and ancestry were assessed. Individuals with the lowest calcification stage of all present molars in stage H were ≥18 years with a likelihood of ≥99.05% in the female (n=388), and ≥99.24% in the male (n=482) population. The lowest calcification stage of all present third molars proved to be useful as an additional reliable criterion for the determination of an age ≥18 years.
Subject(s)
Age Determination by Teeth/methods , Molar, Third/growth & development , Tooth Calcification , Adolescent , Female , Forensic Dentistry , Humans , Male , Molar, Third/diagnostic imaging , Radiography, Panoramic , Retrospective Studies , Young AdultABSTRACT
INTRODUCTION: Anterior open bite cases are very difficult to treat satisfactorily because of their multifactorial aetiology and their very high relapse rate. Dependent on the origin of the anterior open bite malocclusion and the patient's age, there are several treatment possibilities ranging from deterrent appliances, high-pull headgear, fixed appliances with and without extractions to orthognathic surgery, and skeletal anchorage with miniplates or miniscrews. METHODS: The gold standard treatment of skeletal anterior open bite cases is the combined approach of orthodontic treatment with fixed appliances and orthognathic surgery. In recent years, temporary anchorage devices (TAD) have been developed to correct anterior open bites orthodontically. With the introduction of TAD as an effective treatment modality, orthognathic surgery may be avoidable in selected anterior open bite cases. CONCLUSION: This is a relatively new technique and to date there remains a lack of evidence of long-term stability of anterior open bite closure with TAD.
