ABSTRACT
Radioactive iodine in the treatment of Graves' disease has been associated with the development of de novo Graves' ophthalmopathy (GO). In this report, we describe five individuals who required extensive ophthalmic treatment for post-RAI de novo GO.
Subject(s)
Graves Disease/radiotherapy , Graves Ophthalmopathy/diet therapy , Graves Ophthalmopathy/etiology , Iodine Radioisotopes/adverse effects , Iodine Radioisotopes/therapeutic use , Radiation Injuries/diagnostic imaging , Radiation Injuries/etiology , Adult , Diagnosis, Differential , Female , Graves Disease/diagnostic imaging , Humans , Male , Middle Aged , Radiation Injuries/prevention & control , Radiopharmaceuticals/adverse effects , Radiopharmaceuticals/therapeutic use , Singapore , Young AdultABSTRACT
BACKGROUND & AIMS: Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling. METHODS: Mice with either hepatocyte-specific depletion of KLF6 ('ΔHepKlf6') or global KLF6 heterozygosity (Klf6+/-) were fed a high fat diet (HFD) or chow for 8 or 16 weeks. Glucose and insulin tolerance tests were performed to assess insulin sensitivity. Overexpression and knockdown of KLF6 in cultured cells enabled the elucidation of underlying mechanisms. In liver samples from a cohort of 28 NAFLD patients, the expression of KLF6-related target genes was quantified. RESULTS: Mice with global- or hepatocyte-depletion of KLF6 have reduced body fat content and improved glucose and insulin tolerance, and are protected from HFD-induced steatosis. In hepatocytes, KLF6 deficiency reduces PPARα-regulated genes (Trb3, Pepck) with diminished PPARα protein but no change in Pparα mRNA, which is explained by the discovery that KLF6 represses miRNA 10b, which leads to induction of PPARα. In NAFLD patients with advanced disease and inflammation, the expression of miRNA 10b is significantly downregulated, while PEPCK mRNA is upregulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression. CONCLUSIONS: KLF6 increases PPARα activity, whereas KLF6 loss leads to PPARα repression and attenuation of lipid and glucose abnormalities associated with a high fat diet. The findings establish KLF6 as a novel regulator of hepatic glucose and lipid metabolism in fatty liver.
Subject(s)
Fatty Liver/physiopathology , Kruppel-Like Transcription Factors/physiology , PPAR alpha/physiology , Proto-Oncogene Proteins/physiology , Signal Transduction/physiology , Transcriptional Activation/physiology , Animals , Cells, Cultured , Cohort Studies , Diet, High-Fat/adverse effects , Disease Models, Animal , Fatty Liver/etiology , Fatty Liver/metabolism , Glucose/metabolism , Humans , Insulin/metabolism , Kruppel-Like Factor 6 , Kruppel-Like Transcription Factors/deficiency , Kruppel-Like Transcription Factors/genetics , Lipid Metabolism/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease , Phosphoenolpyruvate Carboxykinase (GTP)/metabolism , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/genetics , RNA, Messenger/metabolismABSTRACT
INTRODUCTION: Splenic biopsies are not routinely performed because of the risk of severe hemorrhage. The aim of this study was to explore the feasibility of performing laparoscopic splenic biopsies using a fibrin sealant in pigs and then to translate this technique into the clinical setting. METHOD: Four German Landrace pigs underwent a laparoscopic splenic biopsy using a fibrin sealant to occlude the needle tract. Time to achieve hemostasis and postoperative hemorrhage were assessed. RESULT: The average time to achieve haemostasis was 15 s (range, 8 to 25 s) with no hemorrhage from the needle tract observed. Subsequently this was translated into the clinical setting where a patient also underwent a laparoscopic splenic biopsy without any adverse effect. CONCLUSIONS: Laparoscopic splenic biopsy with the application of a fibrin sealant is a safe and efficient technique.