Effect of atorvastatin on lipoxygenase pathway-related gene expression in an in vitro model of lipid accumulation in hepatocytes.

Lipid accumulation in hepatocytes can result from an imbalance between lipid acquisition and lipid catabolism. In recent years, it has been discovered that eicosanoids derived from arachidonic acid (AA) have the potential to create specialized pro-resolving lipid mediators to actively resolve inflammation, but it is not clear whether AA and lipoxygenases exert effects on hepatic inflammation. Here, the effects of atorvastatin on the expression of cytoplasmic phospholipase A2 (cPLA2) and lipoxygenase pathway genes (ALOX5, ALOX12, ALOX15, and ALOX15B) were evaluated in an in vitro model of palmitic acid (PA)-induced hepatocyte lipid accumulation in McA-RH7777 (McA) cells. Palmitic acid increased cPLA2 expression, intracellular AA levels, and ALOX12 expression (P < 0.05). Atorvastatin at various concentrations had no significant effects on AA levels or on cPLA2, ALOX15, and ALOX15B expressions. ALOX5 was not detected, despite multiple measurements. Pro-inflammatory IL-1ß expression levels were upregulated by PA (P < 0.01) and attenuated by atorvastatin (P < 0.001). TNFα did not differ among groups. The expression levels of anti-inflammatory IL-10 decreased in response to PA (P < 0.05), but were not affected by atorvastatin. In conclusion, in an in vitro model of lipid accumulation in McA cells, atorvastatin reduced IL-1ß; however, its effect was not mediated by AA and the lipoxygenase pathway at the established doses and treatment duration. Further research is required to investigate time-response data, as well as other drugs and integrated cell systems that could influence the lipoxygenase pathway and modulate inflammation in liver diseases.

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, ß-oxidation, and triglyceride hydrolysis.

Corrigendum: Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency.

[This corrects the article on p. 113 in vol. 8, PMID: 28919908.].

Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency.

The inactivation of ribosomal protein S6 kinase 1 (S6K1) recapitulates aspects of caloric restriction and mTORC1 inhibition to achieve prolonged longevity in invertebrate and mouse models. In addition to delaying normative aging, inhibition of mTORC1 extends the shortened lifespan of yeast, fly, and mouse models with severe mitochondrial disease. Here we tested whether disruption of S6K1 can recapitulate the beneficial effects of mTORC1 inhibition in the Ndufs4 knockout (NKO) mouse model of Leigh Syndrome caused by Complex I deficiency. These NKO mice develop profound neurodegeneration resulting in brain lesions and death around 50-60 days of age. Our results show that liver-specific, as well as whole body, S6K1 deletion modestly prolongs survival and delays onset of neurological symptoms in NKO mice. In contrast, we observed no survival benefit in NKO mice specifically disrupted for S6K1 in neurons or adipocytes. Body weight was reduced in WT mice upon disruption of S6K1 in adipocytes or whole body, but not altered when S6K1 was disrupted only in neurons or liver. Taken together, these data indicate that decreased S6K1 activity in liver is sufficient to delay the neurological and survival defects caused by deficiency of Complex I and suggest that mTOR signaling can modulate mitochondrial disease and metabolism via cell non-autonomous mechanisms.

Serum FGF21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is an emerging metabolic regulator associated with glucose and lipid metabolism. However, previous studies of FGF21 have been largely confounded by obesity, and data are limited for advanced outcomes such as coronary artery disease (CAD) and ectopic fat accumulation. We investigated the associations between serum FGF21 concentrations and glucose/lipid metabolism, CAD, and pericardial fat deposition in subjects strictly matched for obesity parameters. DESIGN, PATIENTS AND MEASUREMENTS: We enrolled 189 patients who had undergone cardiac multidetector coronary computed tomography. We measured cardiometabolic parameters and serum FGF21 levels within body mass index (BMI)-matched groups. Correlations and linear regressions were analysed among serum FGF21 levels, pericardial fat volumes and cardiometabolic parameters. Serum FGF21 concentrations were compared in patients with and without diabetes, metabolic syndrome (MS) or CAD. RESULTS: Serum FGF21 concentrations were significantly higher in BMI-matched patients with MS (107·2 ± 83·6 vs 82·1 ± 67·4 ng/l without MS, P < 0·05), but not among those with diabetes (84·3 ± 56·4 vs 96·3 ± 98·9 ng/l without diabetes, P = 0·300) or CAD (89·6 ± 65·8 vs 84·2 ± 83·1 ng/l without CAD, P = 0·633). Serum FGF21 concentrations correlated positively with triglycerides, low-density lipoprotein-cholesterol, insulin, HOMA-IR and pericardial fat volume. They showed an independent association with pericardial fat volume (ß = 0·111 ± 0·053, P < 0·05). CONCLUSIONS: Serum FGF21 concentrations were significantly associated with lipid profiles, insulin resistance, pericardial fat volume and MS, independently of obesity, but not with overt CAD or diabetes.

Plasma FGF21 levels are increased in patients with hypothyroidism independently of lipid profile.

Thyroid hormone is a potent regulator of metabolic and energy homeostasis implicated in various metabolic diseases. Fibroblast growth factor 21(FGF21) is a systemic metabolic regulator known to modulate various biological functions similar to the actions of thyroid hormone. We investigated the differences in plasma FGF21 concentrations in patients with varying thyroid function. Ninety drug-naïve subjects who underwent thyroid evaluation at Seoul National University Bundang Hospital were enrolled and classified into euthyroid, subclinical hypothyroid, and overtly hypothyroid groups. Biochemical markers and plasma FGF21 levels were measured and analyzed. The mean age of the subjects was 42.6 ± 9.1 years. The mean body mass index (BMI), waist circumference, and fasting glucose concentrations were similar between groups. Overtly hypothyroid subjects exhibited significantly higher concentrations of total cholesterol, triglyceride, and LDL-cholesterol than the other groups (p<0.01). Mean plasma FGF21 concentrations in euthyroid, subclinical hypothyroid and overtly hypothyroid groups were 43.2 ± 39.2 pg/mL, 63.6 ± 73.6 pg/mL, and 101.5 ± 74.9 pg/mL, respectively (p<0.01 between groups). Plasma FGF21 concentrations remained significantly higher in overtly hypothyroid subjects after adjusting for serum triglyceride concentrations (p<0.005). Multivariate analysis revealed a significant positive linear relationship between serum TSH concentrations and plasma FGF21 concentrations (ß = 0.192, p = 0.002) and a significant negative linear relationship between free T4 and plasma FGF21 concentrations (ß = -0.382, p = 0.037) after adjusting for gender, BMI and serum concentrations of triglycerides and glucose. Plasma FGF21 levels were significantly increased in patients with hypothyroidism independently of BMI, or lipid or glucose metabolism.

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.

Comparison of regional body composition and its relation with cardiometabolic risk between BMI-matched young and old subjects.

OBJECTIVE: Difference in regional body composition between young and old people may be related with differential cardiometabolic risks. We investigated regional body composition in BMI-matched young and old subjects to compare its relation with cardiometabolic risk. METHODS: We recruited 1:3 gender- and BMI-matched 86 young subjects (mean age 27.3 ± 2.9 years) and 258 older subjects (75.6 ± 8.2 years) from a community. Abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) and muscle area at mid-thigh level were evaluated by computed tomography. Fat depots in the gynoid area and lower extremity were measured by dual energy X-ray absorptiometry. Adiponectin, retinol binding protein-4 (RBP-4), and C-reactive protein (CRP) concentrations, pulse wave velocity (PWV) and ankle-brachial index (ABI) were measured for cardiometabolic risk. RESULTS: VAT was greater in older subjects while SAT was almost the same, resulting in twice higher VAT/SAT ratio in older men and women (1.03 ± 0.37 and 0.57 ± 0.18) than younger counterparts (0.55 ± 0.24 and 0.23 ± 0.23) (both P < 0.01). Fat mass in the gynoid area and lower extremity was smaller in older subjects than younger subjects. The VAT correlated with adiponectin level negatively and RBP-4 level positively while gynoid fat correlated with them in opposite direction. The CRP levels negatively correlated with mid-thigh muscle in older subjects. Older subjects had higher PWV and lower ABI compared to BMI-matched younger counterparts. CONCLUSION: In conclusion, older adults in this cohort had increased visceral fat and decreased gynoid and lower extremity fat, along with less muscle mass. These findings may help explain the worse cardiometabolic profiles in the elderly who have the same BMI as the young.

Factors predicting therapeutic efficacy of combination treatment with sitagliptin and metformin in type 2 diabetic patients: the COSMETIC study.

OBJECTIVE: We assessed the predictive parameters for therapeutic efficacy of initial combination therapy with sitagliptin and metformin in drug-naïve type 2 diabetic patients. DeSIGN, PATIENTS, AND MEASUREMENTS: In this 52-week treatment study, 150 patients (mean age, 54·9 ± 12·5 years) with type 2 diabetes and HbA1c of 7·0-10% were treated with sitagliptin 100 mg once and metformin 500 mg twice daily. To assess the predictive parameters for therapeutic efficacy, a multivariate regression analysis was performed with baseline fasting glucose, insulin, C-peptide, and glucagon levels, homoeostasis model assessment-insulin resistance (HOMA-IR) and ß-cell function (HOMA-B), insulinogenic index (IGI, defined as 30-0 min insulin/30-0 min glucose), and area under the curve for glucose, insulin, and C-peptide obtained after 75-g oral glucose tolerance test. RESULTS: After 52 weeks, mean HbA1c levels and fasting and postload 2-h glucose were significantly decreased from 8·7 ± 1·4% to 7·2 ± 1·3%, 9·2 ± 3·0 to 7·2 ± 1·8 mm, and 17·5 ± 5·1 to 10·9 ± 3·6 mm, respectively (P < 0·01). HOMA-B and IGI increased significantly from 50·3 ± 33·5 to 75·1 ± 32·8 and from 11·3 ± 1·3 to 35·0 ± 6·3 at 52 weeks, respectively (P < 0·01). Multivariate regression analysis indicated that the reduction in HbA1c was significantly associated with high baseline HbA1c, low IGI, and short duration of diabetes after adjusting for age, sex, body mass index, blood pressure, triglycerides, creatinine, high-sensitivity CRP, glucagon, C-peptide, HOMA-B, and HOMA-IR. No severe adverse events were observed. CONCLUSION: These results suggest that drug-naïve type 2 diabetic patients with low ß-cell function would benefit the most from early initial combination therapy of sitagliptin and metformin.

Effect of metabolic syndrome on coronary artery stenosis and plaque characteristics as assessed with 64-detector row cardiac CT.

PURPOSE: To investigate the prevalence and severity of subclinical coronary atherosclerosis and plaque characteristics in asymptomatic subjects according to the presence or absence of metabolic syndrome (MS) with multidetector computed tomography (CT). MATERIALS AND METHODS: This study was approved and the requirement for informed patient consent was waived by the local institutional review board. Degree of coronary artery stenosis, multivessel involvement, and plaque characteristics, as well as coronary artery calcium score (CACS), were assessed with 64-detector row CT in 3000 age- and sex-matched asymptomatic individuals (mean age, 50.2 years ± 8.9 [standard deviation]; age range, 30-79 years). Anthropometric and metabolic profiles were also measured. Multivariate logistic regression analyses were performed to identify variables related to coronary atherosclerosis and plaque types. RESULTS: Subjects with MS had significant coronary artery stenosis (>50% stenosis), multivessel involvement, more positive remodeling, more atherosclerotic coronary segments, and higher CACS than subjects without MS (P < .01 for all). Mixed and noncalcified plaques were also more prominent in subjects with MS than in those without MS (14.2% ± 4.4 vs 7.6% ± 3.1 and 13.1% ± 4.3 vs 7.3% ± 2.8, respectively; P < .01 for both). After adjustment for confounding factors, MS was strongly associated with significant coronary artery stenosis, multivessel involvement, and mixed plaque. CONCLUSION: Multidetector CT is useful in the early diagnosis and evaluation of subclinical coronary atherosclerosis in asymptomatic patients with MS; however, future prospective studies are needed to address the clinical implications of these findings.

Life-threatening hypoglycemia induced by a tyrosine kinase inhibitor in a patient with neuroendocrine tumor: a case report.

We describe a case of a patient who was confronted with two life-threatening conditions: extensive neuroendocrine tumor and hypoglycemia induced by sunitinib administration, as an anti-neoplastic agent. Administration of small dose of prednisolone could prevent severe hypoglycemia and improve glucose homeostasis.

Plasma vaspin concentrations are elevated in metabolic syndrome in men and are correlated with coronary atherosclerosis in women.

OBJECTIVE: Vaspin is visceral adipose-tissue-derived adipokine, which has an insulin-sensitizing effect in obese type 2 diabetic rodent models. As adipokines may serve as a link between visceral adiposity and atherosclerosis, we investigated whether plasma vaspin concentrations were associated with the metabolic syndrome and coronary atherosclerosis. DESIGN AND METHODS: We measured fasting plasma vaspin levels in 81 subjects with the metabolic syndrome and 241 age- and sex-matched control subjects without the metabolic syndrome using the enzyme-linked immunosorbent assay. Multi-detector row cardiac computed tomography was performed to evaluate coronary atherosclerosis. We analysed sex-specific plasma vaspin concentrations according to the presence of the metabolic syndrome and the severity of coronary atherosclerosis. RESULTS: Plasma vaspin concentrations were significantly higher in men with the metabolic syndrome compared with those without the metabolic syndrome [median 0·60 (inter-quartile range 0·40-0·99) ng/ml vs 0·40 (0·26-0·66) ng/ml, P = 0·002]. There was a positive correlation between plasma vaspin concentrations and body mass index, waist circumference, and per cent body fat in men. However, these relationships were not found in women. Plasma vaspin concentrations were associated with the presence and severity of coronary artery stenosis such as higher Agatstone calcium score, number of diseased vessels and characteristics of coronary artery plaque only in women. CONCLUSIONS: Higher plasma vaspin concentrations are significantly associated with metabolic syndrome in men. In women, vaspin concentrations are associated with coronary atherosclerosis. Further studies regarding the role of vaspin in the pathogenesis of obesity and atherosclerosis are required.

Serum fibroblast growth factor-21 concentration is associated with residual renal function and insulin resistance in end-stage renal disease patients receiving long-term peritoneal dialysis.

Fibroblast growth factor-21 (FGF-21) is a new metabolic regulator, which is related to antiobesity and insulin sensitivity in vivo. However, the clinical implication of FGF-21 is poorly understood. To investigate whether FGF-21 may play a role as a metabolic regulator in patients with end-stage renal disease, we measured serum concentrations of FGF-21, inflammatory markers, and metabolic parameters in healthy people (n = 63) and nondiabetic patients receiving peritoneal dialysis (PD, n = 72). The patients were treated with angiotensin receptor blocker for 6 months, and the changes in FGF-21 concentration and metabolic parameters were assessed. Compared with controls, serum FGF-21 concentration was 8 times higher in patients undergoing PD (754.2 ± 463.5 vs 86.9 ± 60.2 pg/mL, P < .001). In controls, only lipid parameters correlated positively with FGF-21 concentration. In contrast, inflammatory markers (interleukin-6, fibrinogen, high-sensitivity C-reactive protein) and homeostasis model assessment of insulin resistance (HOMA-IR) correlated positively and residual renal function correlated inversely with serum FGF-21 concentration in PD patients. In a multivariate analysis adjusting these factors, residual renal function, HOMA-IR, and fibrinogen concentration were independent determinants of serum FGF-21 concentration. After 6-month angiotensin receptor blocker treatment, serum FGF-21 concentration declined significantly by 13% and HOMA-IR and inflammatory markers improved in PD patients. These findings suggest that FGF-21 may play a role in insulin resistance in patients with end-stage renal disease.

Extramedullary peritoneal hematopoiesis combined with tuberculosis in a patient with primary myelofibrosis.

Primary myelofibrosis (PMF) is a myeloproliferative disorder characterized by bone marrow fibrosis or dysmegakaryocytes, extramedullary hematopoiesis, and the presence of JAK2 mutations. We present a 73-year-old man with PMF that had a fulminant clinical course. Peritoneal extramedullary hematopoiesis combined with tuberculosis was found 4 months after the diagnosis. This combination of complications has not been previously reported. These events were followed by rapid leukemic transformation and the patient's death.