Masaki Watanabe

Regulation of PPARγ transcriptional activity in 3T3-L1 adipocytes

PPAR gamma is a member of the nuclear hormone receptor superfamily and functions as a transcriptional regulator of genes linked to adipogenesis and lipid metabolism. The regulation of PPAR gamma activity by insulin signaling molecules in adipocytes has yet to be clarified. Therefore, it is important to measure endogenous PPAR gamma transcriptional activities in response to various stimuli in adipocytes. Herein, with a transcription reporter assay using recombinant adenovirus vectors expressing PPRE (PPAR responsive elements)-reporter genes, we established a novel system for measuring endogenous PPAR gamma transcriptional activity in 3T3-L1 adipocytes. By means of this system, a marked increase (8.5-fold) in PPAR gamma transcriptional activity was detected after treatment with 10(-6)M pioglitazone, a thiazolidinedione (TZD), indicating that this system can measure PPAR gamma activity accurately. Furthermore, MAPK activation, achieved by overexpressing constitutively activated MEK1, inhibited PPAR gamma transcriptional activity. In contrast, treatment with PKA stimulators markedly increased PPAR gamma activity. Interestingly, PI 3-kinase overexpression resulted in a marked decrease in PPAR gamma activity. These observations have important implications for understanding the regulation of PPAR gamma transcriptional activity.

Hepatic failure during anabolic steroid therapy.

Question: A 78-yearold man was referred to our center because of rapidly worsening liver dysfunction. He was diagnosed as having idiopathic thrombocytopenic purpura at the age of 68, and has been treated with an anabolic steroid, danazol, for nearly 2 years. On admission, his physical examination was unremarkable except for marked jaundice, appetite loss, and general fatigue. Laboratory studies showed the following: white cell count, 10000/mm3; total bilirubin, 11.7 mg/dL; aspartate aminotransferase, 95 IU/L; alanine aminotransferase, 185 IU/L; lkaline phosphatase, 677 IU/L; and gamma-glutamyl transpeptidase, 2152 IU/L. Viral markers for hepatitis B or hepatitis C were all egative, and serologic tests for autoantibodies were also all negative. He had no history of heavy alcohol consumption. Abdominal ltrasonography and computed tomography showed no evidence to substantiate a diagnosis of obstructive jaundice or hepatic tumor. owever, magnetic resonance imaging (MRI) showed that both liver lobes had low signal intensity on T1 weighted images (Figure A) and igh signal intensity on T2 weighted images (Figure B). After admission, his clinical condition deteriorated rapidly. He received palliative are and died of hepatic failure on hospital day 26. What is the diagnosis? See the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

A rare case of ulcerative colitis exacerbated by VZV infection

A 16-years old man with severe ulcerative colitis (UC) was admitted to our hospital. After initiating treatment with corticosteroid for UC, chicken pox appeared. At the same time of appearance of chicken pox, the disease activity of UC was exacerbated. After initiating the treatment with acyclovir, both chicken pox and UC improved. Because colonoscopic findings revealed the remaining of moderately active UC, initiating the treatment with infliximab could induce clinical remission of UC without relapse of varicella-zoster virus (VZV) infection. This is a very rare case of UC with concomitant VZV infection. According to our report, the vaccination for VZV prior to immunosuppressive treatments would be necessary for VZV naïve patients with UC.

Effects of telmisartan on insulin resistance in Japanese type 2 diabetic patients

OBJECTIVE PPARgamma agonists are widely used in type 2 diabetic patients to reduce insulin resistance. Recently, telmisartan, an AT1 receptor antagonist, was reported to function as a partial agonist of PPARgamma based on in vitro experiments. The aim of the present study was to investigate whether the PPARgamma enhancing activity of telmisartan is exerted clinically in diabetic patients. METHODS We compared the effects of telmisartan with those of candesartan, on insulin sensitivity, the serum levels of various adipocytokines and oxidative stress. PATIENTS In total, 85 Japanese type 2 diabetic patients with hypertension, maintained on 8 mg per day of candesartan, were randomly assigned to the TM group (candesartan switched to 40 mg of telmisartan, n=38) or the CD group (no treatment change, n=47). RESULTS After 3 months, oxidized lipids were significantly decreased only in the TM group. Although the homeostasis assessment model of insulin resistance (HOMA-R) tended to be improved and serum concentrations of HDL-cholesterol and HMW adiponectin tended to be increased only in the TM group, these alterations were too small to be significant by unpaired t-test. Interestingly, in subgroup analysis, the alterations of HOMA-R, serum concentrations of oxidized lipids, and HMW adiponectin were more apparent in obese TM group subjects and the changes reached statistical significance. CONCLUSION Switching from candesartan to telmisartan in obese subjects increases serum adiponectin and improves both insulin resistance and oxidative stress, while these effects were not statistically apparent in the total patient population. These results support the idea that telmisartan exerts its PPARgamma enhancing activity clinically in obese type 2 diabetic patients.