The Effects of PPAR Agonists on Atherosclerosis and Nonalcoholic Fatty Liver Disease in ApoE−/−FXR−/− Mice

Background@#Farnesoid X receptor (FXR), a bile acid–activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency. @*Methods@#En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)−/− and ApoE−/−FXR−/− mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice. @*Results@#Compared with ApoE−/− mice, ApoE−/−FXR−/− mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE−/−FXR−/− mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver). @*Conclusion@#Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.

Effects of FXR Deficiency and Pioglitazone on Atherosclerosis in ApoE-Knockout Mice / 대한내과학회지

BACKGROUND/AIMS: Both the farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) play important roles in lipid metabolism and atherosclerosis. We investigated the interaction between FXR and PPARgamma. METHODS: Apolipoprotein E knockout (ApoE-/-) mice and FXR knockout (FXR-/-) mice were crossed to generate ApoE-/-FXR-/- mice. The mice were divided into ApoE-/-, ApoE-/-FXR-/-, and ApoE-/-FXR-/- + pioglitazone groups. All mice were fed a high-fat, high-cholesterol diet for 12 weeks. The ApoE-/-FXR-/- + pioglitazone group was also treated with pioglitazone, 20 mg/kg body weight. Body weight, blood glucose level, lipid profile, and liver enzyme levels were measured. To evaluate atherosclerotic lesions, the aorta was stained with Oil red O. RESULTS: There were no differences in body weight or blood glucose level among the three groups. The serum lipid concentration and liver enzyme levels increased in the ApoE-/-FXR-/- group compared with the ApoE-/- group (p < 0.01). The ApoE-/-FXR-/- + pioglitazone group had lower high-density lipoprotein (HDL) (55 +/- 4 vs. 28 +/- 2 mg/dL, p < 0.01) and low-density lipoprotein (LDL) (797 +/- 26 vs. 682 +/- 47 mg/dL, p = 0.04) cholesterol than the ApoE-/-FXR-/- group. The respective percentages of aortic atherosclerotic plaques in the ApoE-/-, ApoE-/-FXR-/-, and ApoE-/-FXR-/- + pioglitazone groups were 2.7 +/- 0.2%, 7.7 +/- 1.2%, and 18.6 +/- 1.0%. In ApoE-/-FXR-/- mice, the administration of pioglitazone significantly increased the number of atherosclerotic lesions (p = 0.02). CONCLUSIONS: Pioglitazone increased the number of atherosclerotic plaques in ApoE-/-FXR-/- mice. This suggests that when FXR is inhibited, the activation of PPARgamma can aggravate atherosclerosis.

Preoperative Predictive Factors for Parathyroid Carcinoma in Patients with Primary Hyperparathyroidism

This study was conducted to review the clinical characteristics of parathyroid carcinoma (PC) and to evaluate potential preoperative predictive factors for PC in patients with primary hyperparathyroidism (PHPT). We performed a retrospective review of electronic medical records of 194 patients with pathologically confirmed PHPT in affiliated teaching hospitals of Seoul National University from January 2000 to March 2011. Adenoma was diagnosed in 171 patients, hyperplasia in 12, and carcinoma in 11. Several biochemical measurements were higher in patients with PC than in patients with benign disease, including serum total calcium (P < 0.001), intact parathyroid hormone (P = 0.003), and alkaline phosphatase (ALP) (P < 0.001). Tumors were larger in PC than in benign disease (P < 0.001). Multivariate analysis revealed that serum ALP level (P < 0.001) and tumor size were associated with PC (P = 0.03). Tumor size and serum ALP level were evaluated as preoperative predictive factors for PC using ROC analyses: a tumor size of 3.0 cm (sensitivity 90.9%, specificity 92.1%) and serum ALP level of 285 IU/L (83.3%, 97.0%) had predictive value for the diagnosis of PC in patients with PHPT. In conclusion, elevated serum ALP and a large parathyroid mass at the time of diagnosis can be helpful to predict PC in patients with PHPT.

Characterization of Incidentally Detected Adrenal Pheochromocytoma

BACKGROUND: In approach to an adrenal incidentaloma, early exclusion of pheochromocytoma is clinically important, due to the risk of catecholamine crisis. The aims of this study are to investigate the characteristics of incidentally detected pheochromocytomas, compared with that of the other adrenal incidentalomas, and to compare these characteristics with those of symptomatic pheochromocytomas. METHODS: In this retrospective study, we reviewed the medical records of 198 patients with adrenal incidentaloma from 2001 to 2010. We analyzed the clinical, laboratory and radiological data of pheochromocytomas, in comparison with those of the other adrenal incidentalomas. We also compared the characteristics of these incidentally detected pheochromocytomas with the medical records of 28 pathologically proven pheochromocytomas, diagnosed based on typical symptoms. RESULTS: Among the 198 patients with adrenal incidentaloma, nineteen patients were diagnosed with pheochromocytoma. Pheochromocytomas showed larger size and higher Hounsfield unit at precontrast computed tomography (CT) than did non-pheochromocytomas. All pheochromocytomas were larger than 2.0 cm, and the Hounsfield units were 19 or higher in precontrast CT. When both criteria of size > 2.0 cm and Hounsfield unit > 19 were met, the sensitivity and specificity for the diagnosis of pheochromocytoma were 100% and 79.3%, respectively. Compared with patients with pheochromocytoma, diagnosed based on typical symptoms, patients with incidentally detected pheochromocytoma were older, presented less often with hypertension, and showed lower levels of 24-hour urine metanephrine. CONCLUSION: Adrenal incidentaloma with < 2.0 cm in size or < or = 19 Hounsfield units in precontrast CT imaging was less likely to be a pheochromocytoma. Patients with incidentally discovered pheochromocytoma showed lower catecholamine metabolites, compared with those patients with symptomatic pheochromocytoma.

Post-transplantation Osteoporosis / 대한이식학회지

Transplantation has become an established treatment in many end-stage organ diseases and hematologic diseases. The survival rate after transplantation has greatly improved due to the development of newer immunosuppressive drugs bringing the issues of post-transplantation complications to light. Osteoporosis and osteoporosis-related fragility fractures are feared complications, greatly influencing the quality of life in transplant patients. In addition to the conventional risk factors for osteoporosis, post-transplantation osteoporosis is caused by factors related to end-stage organ disease prior to transplantation and immunosuppressive therapy after transplantation. Since the rate of bone loss in post-transplantation osteoporosis is thought to be at the greatest immediately following transplantation, early measures need to be taken to prevent and treat post-transplantation osteoporosis. Both conventional and newer therapeutics for osteoporosis are largely being studied and used in practice for the prevention and treatment of post-transplantation osteoporosis.

Post-transplantation Osteoporosis / 대한이식학회지

Transplantation has become an established treatment in many end-stage organ diseases and hematologic diseases. The survival rate after transplantation has greatly improved due to the development of newer immunosuppressive drugs bringing the issues of post-transplantation complications to light. Osteoporosis and osteoporosis-related fragility fractures are feared complications, greatly influencing the quality of life in transplant patients. In addition to the conventional risk factors for osteoporosis, post-transplantation osteoporosis is caused by factors related to end-stage organ disease prior to transplantation and immunosuppressive therapy after transplantation. Since the rate of bone loss in post-transplantation osteoporosis is thought to be at the greatest immediately following transplantation, early measures need to be taken to prevent and treat post-transplantation osteoporosis. Both conventional and newer therapeutics for osteoporosis are largely being studied and used in practice for the prevention and treatment of post-transplantation osteoporosis.

Pharmacothearpy of Adolescents with Diabetes / 임상당뇨병

Diabetes in adolescents is gaining importance since most type 1 diabetes onsets at young age, and the prevalence of type 2 diabetes is increasing in parallel with childhood obesity. Pharmacotherapy of adolescents with diabetes requires special attention because adolescence is characterized by physical and emotional growth due to a unique hormonal influence. However, a scarcity of data exists on this issue, and insulin and metformin remain as the mainstay of pharmacotherapy in adolescents with diabetes. More studies on the efficacy and safety of available medications are needed to advance pharmacotherapy in this unique population.

A case of adult nesidioblastosis mimicking an insulinoma and autoimmune hypoglycemia / 대한내과학회지

Hyperinsulinemic hypoglycemia in the absence of exogenous insulin use is caused by disorders such as insulinoma, diffuse beta-cell hyperplasia/nesidioblastosis, and autoimmune hypoglycemia. Nesidioblastosis is a rare cause of hypoglycemia in adults, accounting for 0.5~7.0% of organic hyperinsulinemia cases. Although pancreatic resection is considered the best treatment modality for curing nesidioblastosis, there is no consensus regarding the indications for and extent of the surgery due to its high risk and complication rate. A 75-year-old woman presented with an altered mental state, a mass suspected of being an insulinoma, and insulin receptor antibodies. The patient underwent surgery because of recurrent life-threatening hypoglycemia. Postoperative pathology of her pancreas revealed nesidioblastosis.