Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine.

Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Apoa5 mRNA. Consistently, in vitro studies indicated that olanzapine increased medium triglyceride levels and decreased medium apoA5 levels in a dose-dependent manner in human HepG2 cells and primary mouse hepatocytes. Whereas the olanzapine treatment increased hepatic apoA5 protein in vitro, without effects on hepatic APOA5 mRNA. Of note, olanzapine increased the co-localization between apoA5 protein and accumulated lipid droplets in hepatocytes, as opposed to at the hepatocellular plasma membrane, in mouse liver as demonstrated by fluorescence staining. Therefore, our study indicated that short-term use of olanzapine induced hypertriglyceridemia due to defects of sorting and secretion of hepatic apoA5.

Case Report: A Mysterious Giant Thrombus in the Right Atrium in a Patient With Dilated Cardiomyopathy.

An isolated right atrial thrombus is a life-threatening entity that is extremely rare in patients with dilated cardiomyopathy (DCM), which is characterized by a reduced left ventricular function and consequent left ventricular thrombosis. Here, we present the case of a mysterious isolated giant right atrial thrombus in a male patient with DCM. The presence of deep vein thrombosis prompted us to investigate for other underlying diseases for his right atrial thrombus. Interestingly, the elevation of two tumor markers indicated the likelihood of cancer-associated thrombosis. Further, the computed tomography demonstrated a spiculated mass in the lower right lung that was confirmed by an endobronchial biopsy as lung squamous cell carcinoma. Consequently, the giant thrombus in the right atrium should be attributed principally to lung squamous cell carcinoma on the background of DCM. After 3 weeks of enoxaparin, the echocardiogram indicated partial resolution of the thrombus. However, the patient suffered sudden death due to pulmonary embolism.

A Rare Case of Isolated Right Ventricular Non-compaction With the Novel TTN Mutation.

Isolated right ventricular non-compaction (RVNC) is rare yet life-threatening if left untreated, especially when accompanied by ventricular tachycardia. We describe a rare case of isolated RVNC, presenting as a prominent and excessive trabeculation of the right ventricle (RV), with an abnormal electrocardiogram. The transthoracic echocardiography, computed tomography, and ventricular angiography results clearly demonstrated an isolated spongy RV, both anatomically and functionally. Genetic testing identified a missense mutation of TTN. Combined, the diagnosis of RVNC was established. The subsequent combination of heart failure therapy, antiarrhythmic, and anticoagulation therapy were effective with a favorable outcome. This case report describes the possible etiology, manifestation, characteristic images, and problematic diagnostic criteria of the isolated RVNC. This case also emphasizes the necessity for comprehensive cardiac screening in familial cardiomyopathy.

Xuezhikang contributes to greater triglyceride reduction than simvastatin in hypertriglyceridemia rats by up-regulating apolipoprotein A5 via the PPARα signaling pathway.

Xuezhikang (XZK), an extract of Chinese red yeast rice, is recommended as an optimal choice for patients with coronary heart disease (CHD) with markedly elevated triglyceride (TG) levels. This study was designed to compare the hypotriglyceridemic effects between XZK and simvastatin. The role of apolipoprotein A5 (apoA5), a key regulator of TG metabolism and a target gene of peroxisome proliferator-activated receptor α (PPARα), was to be identified in XZK-related hypotriglyceridemic actions. For these goals, hypertriglyceridemia of rats was induced by a high-fructose diet. In order to investigate the hypotriglyceridemic effects of XZK and simvastatin on these animals based on an equivalent low-density lipoprotein cholesterol (LDL-C) lowering power, we titrated their doses (XZK 80 mg/kg/d versus simvastatin 1 mg/kg/d) according to plasma LDL-C reduction of rats. Similarly, we titrated the target doses of the two agents (XZK 500 µg/ml versus simvastatin 10 µM) according to hepatocyte LDL receptor expressions, and then compared the effects of the two agents on TG and apoA5 of hepatocytes in vitro. Our results showed that XZK (80 mg/kg/d) had higher hypotriglyceridemic performance than simvastatin (1 mg/kg/d) on these animals albeit their equivalent LDL-C lowering power. Higher plasma apoA5 levels and hepatic apoA5 expressions were observed in rats treated with XZK (80 mg/kg/d) than simvastatin (1 mg/kg/d). Further, XZK (80 mg/kg/d) contributed to higher hepatic PPARα expressions of rats than simvastatin (1 mg/kg/d). Although the two agents led to an equivalent up-regulation of LDL receptors of hepatocytes, more TG reduction and apoA5 elevation were detected in hepatocytes treated with XZK (500 µg/ml) than simvastatin (10 µM). However, PPARα knockdown eliminated the above effects of XZK on hepatocytes. Therefore, our study indicates that XZK has greater hypotriglyceridemic performance than simvastatin in the setting of an equivalent LDL-C lowering power, which is attributed to more apoA5 up-regulation by this agent via the PPARα signaling pathway.

Metformin improves nonalcoholic fatty liver disease in obese mice via down-regulation of apolipoprotein A5 as part of the AMPK/LXRα signaling pathway.

Apolipoprotein A5 (apoA5) has been implicated in the formation of hepatocyte lipid droplets, a histological hallmark of non-alcoholic fatty liver disease (NAFLD). Recent evidence demonstrated that liver X receptor α (LXRα), a transcription factor involved in down-regulation of APOA5 mRNA, is activated by AMP-activated protein kinase (AMPK) that contributes to metformin-related antihyperglycemic effects. In this study we investigated the role of apoA5 and AMPK/LXRα signaling pathway in metformin-related improvement of NAFLD. Leptin-deficient (ob/ob) obese mice with NAFLD were treated with metformin, and signaling pathways were compared with non-metformin treated mice. Additionally, we determined cellular apoA5 and triglyceride (TG) levels in mouse hepatocytes in vitro and the effects of metformin, with or without an AMPK inhibitor or LXRα siRNA, on these levels. We found that metformin dose-dependently ameliorated hepatosteatosis and liver dysfunction in ob/ob mice, with a significant reduction in hepatic apoA5 expression and TG level. Metformin also dose-dependently increased phosphorylation of hepatic AMPK and LXRα in ob/ob mice. Similarly, metformin decreased apoA5 expression and TG level in mouse hepatocytes, with increased phosphorylation of cellular AMPK and LXRα. Addition of AMPK inhibitor or siRNA knockdown of LXRα significantly attenuated metformin-induced down-regulation of cellular apoA5 expression and TG level. AMPK inhibitor also significantly inhibited metformin-induced LXRα phosphorylation in these hepatocytes. Therefore, our findings indicate that metformin improves obesity-related NAFLD via inhibition of hepatic apoA5 synthesis as part of the AMPK/LXRα signaling pathway.

Metformin ameliorates obesity-associated hypertriglyceridemia in mice partly through the apolipoprotein A5 pathway.

INTRODUCTION: Apolipoprotein A5 (apoA5) is a key regulator of triglyceride (TG) metabolism. This study is to investigate the role of apoA5 in obesity-associated hypertriglyceridemia and metformin-related hypotriglyceridemic actions. METHODS: Two obese mouse models, including high-fat diet-induced obese mice and ob/ob obese mice, were adopted. The effects of low- and high-dose metformin were determined on plasma and hepatic TG and apoA5 of these obese mice. Besides, the effects of metformin on TG and apoA5 were also detected in mouse and human hepatocytes in vitro. RESULTS: (1) Plasma apoA5 levels in the obese mice were markedly elevated and positively correlated with TG. Hepatic TG contents and apoA5 expressions were also remarkably increased in the obese mice. (2) Metformin dose-dependently decreased hepatic and plasma TG and apoA5 in the obese mice. Similarly, metformin dose-dependently reduced cellular TG contents and apoA5 expressions in hepatocytes in vitro. Compared to APOA5 knock-down (KD), metformin plus APOA5 KD resulted in more TG reduction of hepatocytes. CONCLUSION: Increased hepatic and plasma apoA5 could be a result of obesity-associated hypertriglyceridemia, and metformin displays hypotriglyceridemic effects on obese mice partly via the apoA5 pathway.

Inflammation Activation Contributes to Adipokine Imbalance in Patients with Acute Coronary Syndrome.

Inflammation can be activated as a defensive response by the attack of acute coronary syndrome (ACS) for ischemic tissue injury. The aim of the present study was to investigate the impact of ACS-activated inflammation on adipokine imbalance and the effects of statins on the crosstalk between inflammation and adipokine imbalance during ACS. In this study, 586 subjects were categorized into: (1) control group; (2) SA (stable angina) group; and (3) ACS group. Circulating levels of hs-CRP, adiponectin and resistin were measured by ELISA. Furthermore, forty C57BL/6 mice were randomized into: sham, AMI, low-statin (atorvastatin, 2 mg/kg/day) and high-statin (atorvastatin, 20 mg/kg/day) group. After 3 weeks, AMI models were established by surgical coronary artery ligation. Circulating levels and adipose expressions of adiponectin and resistin were assessed in animals. Besides, we investigate the effects of atorvastatin on ox-LDL-induced adipokine imbalance in vitro. As a result, we found that ACS patients had higher hs-CRP and resistin levels and lower adiponectin levels. Our correlation analysis demonstrated hs-CRP concentrations were positively correlated with resistin but negatively with adiponectin levels in humans. Our animal findings indicated higher circulating hs-CRP and resistin levels and lower adiponectin levels in AMI mice. Atorvastatin pre-treatment dose-dependently decreased hs-CRP and resistin levels but increased adiponectin levels in mice. The consistent findings were observed about the adipose expressions of resistin and adiponectin in mice. In study in vitro, ox-LDL increased cellular resistin expressions and otherwise for adiponectin expressions, which dose-dependently reversed by the addition of atorvastatin. Therefore, our study indicates that the ACS attack activates inflammation leading to adipokine imbalance that can be ameliorated by anti-inflammation of atorvastatin.

The influence of statin-fibrate combination therapy on lipids profile and apolipoprotein A5 in patients with acute coronary syndrome.

BACKGROUND: Statin-fibrate combination therapy has been used to treat patients with acute coronary syndrome (ACS) complicated by elevated triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL-C). The purpose of this study was to evaluate the influence of the combination therapy on lipids profile and apolipoprotein A5 (apoA5) level in patients with ACS. METHODS: One hundred and four patients with ACS were recruited and randomly assigned into two groups: one was statin group (n = 52), given atorvastatin (20 mg QN) or other statins with equivalent dosages; the other was combination group (n = 52), given the same dose of statin plus bezafibrate (200 mg BID). Follow-up visits were scheduled at the end of 6 and 12 weeks post treatment. Serum apoA5 levels were determined using a commercial available ELISA kit. RESULTS: (1) Compared with that of statin monotherapy, statin-bezafibrate combination treatment not only resulted in a significant reduction of TG, TC and LDL-C levels, (all p < 0.05), but also led to increases in HDL-C and apoA5 levels (p < 0.05).(2) The percentage changes of TC, TG, LDL-C and apoA5 levels in both groups were even bigger at 12 weeks after treatment than that at 6 weeks (all p < 0.05). Similarly, the rates of achieving lipid-control target were higher in statin-bezafibrate combination treatment group than those in statin monotherapy group (all p < 0.05).(3) Spearman rank correlation analysis showed that the pre-treatment apoA5 level was positively correlated with TG (r = 0.359, p = 0.009). However, a negative correlation was observed between apoA5 and TG (r = -0.329, p = 0.017) after 12 weeks treatment. CONCLUSIONS: Statin and fibrate combination therapy is more effective than statin alone in achieving a comprehensive lipid control for ACS patients. Serum apoA5 elevation after statin and fibrate combination treatment could be due to the synergistic effect of both drugs on hypertriglyceridemia control.

[Statin reduced triglyceride level via activating peroxisome proliferator activated receptor α and upregulating apolipoprotein A5 in hypertriglyceridemic rats].

OBJECTIVE: to explore the potential role of apolipoprotein A5 (apoA5) on the hypertriglyceridemia (HTG)-lowering effects of statin. METHODS: twenty-four Sprague-Dawley rats were randomized into 3 groups: (1) control group (n = 8), with no special treatment; (2) HTG group (n = 8), treated with 10% fructose water for 6 weeks; (3) statin group (n = 8), treated with 10% fructose water for 2 weeks and cotreated with atorvastatin 10 mg×kg(-1)×d(-1) for another 4 weeks. Body weight, fasting plasma lipids and the hepatic expressions of apoA5 and peroxisome proliferator activated receptor (PPAR)α were determined. In separate in vitro experiments, we tested the effects of atorvastatin on TG and the expressions of apoA5 and PPARα in HepG2 cells. RESULTS: (1) at 6 weeks, plasma TG was higher in rats in HTG group than in controls, which was significantly reduced in statin group (both P < 0.05). (2) Rat hepatic apoA5 expression in HTG group was significantly lower than in control group and was significantly higher in statin group than in HTG group (both P < 0.05). (3) Similarly, rat PPARα mRNA expression in HTG group was lower than in control group and was higher in statin group than in HTG group (both P < 0.05). (4) Statin significantly upregulated the expressions of apoA5 and PPARα and decreased TG in HepG2 cells. The above effects induced by statin was blocked in the presence of PPARα inhibitor. CONCLUSIONS: upregulation of apoA5 expression contributes to TG lowering effect of statin via PPARα signaling pathway.

Decreased apolipoprotein A5 is implicated in insulin resistance-related hypertriglyceridemia in obesity.

Hypertriglyceridemia is associated insulin resistance in obese people. Recently identified apolipoprotein A5 (apoA5) is involved in triglyceride (TG) metabolism. This study was to investigate the role of apoA5 in insulin resistance-related hypertriglyceridemia in obesity. 682 participants including 340 non-obese individuals and 342 obese individuals were recruited in this study. Plasma apoA5 levels were measured. The insulin resistance in participants was assessed by homeostasis model assessment of insulin resistance (HOMA-IR). An insulin resistant and hypertriglyceridemic rat model was established by high-fructose diet with obese Zucker rats as positive controls. Besides, two insulin resistant models in vitro were induced by insulin and tumor necrosis factor-alpha (TNFalpha) in HepG2 cells. Obese participants had lower plasma apoA5 levels. Plasma apoA5 levels were inversely correlated with TG, body mass index and HOMA-IR in humans. Furthermore, hepatic and plasma apoA5 reduced in fructose-fed rats whereas no significant changes of apoA5 were observed in obese Zucker rats. In addition, treatment of HepG2 cells with insulin and TNFalpha decreased apoA5 expression and increased TG content. Thus, decreased apolipoprotein A5 is implicated in insulin resistance-related hypertriglyceridemia in obesity.

Atorvastatin and fenofibrate increase apolipoprotein AV and decrease triglycerides by up-regulating peroxisome proliferator-activated receptor-alpha.

BACKGROUND AND PURPOSE: Combining statin and fibrate in clinical practice provides a greater reduction of triglycerides than either drug given alone, but the mechanism for this effect is poorly understood. Apolipoprotein AV (apoAV) has been implicated in triglyceride metabolism. This study was designed to investigate the effect of the combination of statin and fibrate on apoAV and the underlying mechanism(s). EXPERIMENTAL APPROACH: Hypertriglyceridaemia was induced in rats by giving them 10% fructose in drinking water for 2 weeks. They were then treated with atorvastatin, fenofibrate or the two agents combined for 4 weeks, and plasma triglyceride and apoAV measured. We also tested the effects of these two agents on triglycerides and apoAV in HepG2 cells in culture. Western blot and reverse transcription polymerase chain reaction was used to measure apoAV and peroxisome proliferator-activated receptor-alpha (PPARalpha) expression. KEY RESULTS: The combination of atorvastatin and fenofibrate resulted in a greater decrease in plasma triglycerides and a greater increase in plasma and hepatic apoAV than either agent given alone. Hepatic expression of the PPARalpha was also more extensively up-regulated in rats treated with the combination. A similar, greater increase in apoAV and a greater decrease in triglycerides were observed following treatment of HepG2 cells pre-exposed to fructose), with the combination. Adding an inhibitor of PPARalpha (MK886) abolished the effects of atorvastatin on HepG2 cells. CONCLUSIONS AND IMPLICATIONS: A combination of atorvastatin and fenofibrate increased apoAV and decreased triglycerides through up-regulation of PPARalpha.

Elevated plasma apolipoprotein AV in acute coronary syndrome is positively correlated with triglyceride and C-reactive protein.

BACKGROUND: Increased triglyceride (TG) occurs in patients with acute coronary syndrome (ACS), and apolipoprotein AV (apoAV) has been shown to lower TG levels. In the present study, we investigated plasma apoAV level and its relationship with TG and C-reactive protein (CRP) in ACS patients. METHODS: A total of 459 subjects were recruited and categorized into control group (n = 116), stable angina (SA) group (n = 115), unstable angina group (n = 116) and acute myocardial infarction group (n = 112). Plasma apoAV level was measured by a sandwich ELISA assay. RESULTS: Compared with controls ((100.27 +/- 22.44) ng/ml), plasma apoAV was decreased in SA patients ((76.54 +/- 16.91) ng/ml) but increased in patients with unstable angina ((330.89 +/- 66.48) ng/ml, P < 0.05) or acute myocardial infarction ((368.66 +/- 60.53) ng/ml, P < 0.05). Inverse correlations between apoAV and TG were observed in the control or stable angina groups (r = -0.573 or -0.603, respectively, P < 0.001), whereas positive correlations were observed in the patients with unstable angina or acute myocardial infarction (r = 0.696 or 0.690, respectively, P < 0.001). Furthermore, a positive relationship between apoAV and CRP was observed in the ACS patients but not in the non-ACS subjects. CONCLUSION: The plasma apoAV concentration is increased and positively correlates with TG and CRP in ACS patients.

Association of plasma apolipoprotein AV with lipid profiles in patients with acute coronary syndrome.

Dyslipidemia is common in patients with acute coronary syndromes (ACS) but the mechanism remains unclear. Apolipoprotein AV (apoAV), a novel member of apolipoprotein family, is involved in lipid metabolism. This study was to investigate plasma apoAV level and its association with lipids and high-sensitivity C-reactive protein (hs-CRP) in ACS patients. ACS patients (n=228) and healthy volunteers (n=232) were included. Plasma apoAV levels were measured by an ELISA method. Compared with controls, ACS patients had higher plasma apoAV, hs-CRP, triglycerides, total cholesterol and LDL cholesterol, as well as lower HDL cholesterol. Interestingly, a positive correlation was observed between apoAV and triglycerides in ACS patients, as compared with a negative correlation in controls. Notably, logistic regression analysis showed that plasma apoAV level was an independent predictor of ACS (OR=0.82, 95% CI 0.70-0.95, p<0.05). Furthermore, both apoAV and triglycerides were positively associated with hs-CRP in ACS patients. However, no significant correlations between apoAV and cholesterol including total cholesterol, HDL cholesterol and LDL cholesterol were observed in ACS patients. Thus, apoAV is an independent predictor of ACS although increased plasma apoAV level is positively correlated with triglycerides in ACS patients. Moreover, plasma cholesterol levels are not influenced by apoAV in ACS patients.

[Increased serum apolipoprotein A5 in patients with acute coronary syndrome].

OBJECTIVE: To explore the relationship between serum apolipoprotein A5 (ApoA5) and lipid profile or high sensitive C-reactive protein (hs-CRP) in patients with acute coronary syndrome (ACS). METHODS: Serum apoA5 and hs-CRP levels were measured by ELISA and immunoturbidimetry in control subjects (n = 232), patients with stable angina (SA, n = 127), unstable angina (UA, n = 116) and acute myocardial infarction (AMI, n = 112). Triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were also measured. RESULTS: Compared with controls [(108.7 +/- 23.2) microg/L] and SA patients [(78.3 +/- 20.2) microg/L], serum ApoA5 level was significantly increased in UA [(340.6 +/- 63.5) microg/L] and AMI patients [(373.2 +/- 73.8) microg/L] (all P < 0.05). ApoA5 was positively correlated with TG (r = 0.63 and 0.67, respectively, all P < 0.05) and hs-CRP (r = 0.57 and 0.55, respectively, all P < 0.05) in UA and AMI patients but there were no significant correlations between ApoA5 and TC, HDL-C and LDL-C in ACS patients (all P > 0.05). CONCLUSION: Increased serum apoA5 level and the positive correlation between ApoA5 and serum TG and hs-CRP in ACS patients might reflect increased inflammation responses in ACS patients.

Oxidized low-density lipoprotein: a double-edged sword on atherosclerosis.

It is well known that atherosclerosis is closely related to lipoprotein metabolism, particularly to the low density lipoprotein (LDL). LDL becomes atherogenic after undergoing oxidation by vascular cells, that transform them into highly bioreactive oxidized LDL (oxLDL). oxLDL is generally though to be involved in foam cell formation, and trigger an array of proatherogenic events. However, there are accumulating evidences that low levels of oxLDL can be atheroprotective through its cytoprotection, modulation of immunity and activation of reverse cholesterol transport. Thus, oxLDL may exert biphasic effects on atherosclerosis, just like a doubled-edged sword.