Fenofibrate, an agonist for peroxisome proliferator-activated receptor alpha (PPAR-α), lowers blood pressure, but whether this action is mediated via baroreflex afferents has not been elucidated. In this study, the distribution of PPAR-α and PPAR-γ was assessed in the nodose ganglion (NG) and the nucleus of the solitary tract (NTS). Hypertension induced by drinking high fructose (HFD) was reduced, along with complete restoration of impaired baroreceptor sensitivity, by chronic treatment with fenofibrate. The molecular data also showed that both PPAR-α and PPAR-γ were dramatically up-regulated in the NG and NTS of the HFD group. Expression of the downstream signaling molecule of PPAR-α, the mitochondrial uncoupling protein 2 (UCP2), was up-regulated in the baroreflex afferent pathway under similar experimental conditions, along with amelioration of reduced superoxide dismutase activity and increased superoxide in HFD rats. These results suggest that chronic treatment with fenofibrate plays a crucial role in the neural control of blood pressure by improving baroreflex afferent function due at least partially to PPAR-mediated up-regulation of UCP2 expression and reduction of oxidative stress.
Afferent Pathways ; drug effects ; Animals ; Antihypertensive Agents ; pharmacology ; Baroreflex ; drug effects ; Blood Pressure ; drug effects ; Fenofibrate ; pharmacology ; Male ; Oxidative Stress ; drug effects ; PPAR gamma ; drug effects ; metabolism ; Rats, Sprague-Dawley ; Signal Transduction ; drug effects ; Transcriptional Activation ; drug effects ; Uncoupling Protein 2 ; drug effects ; metabolism ; Up-Regulation

PURPOSE: To determine the relationship of illnesses and medical drug consumption with the occurrence of traffic accidents among truck and bus drivers. METHODS: This is a cross-sectional study on truck and bus drivers in Tehran, Iran. The criteria for participating in this study were: married males over 30 years old, driving license in grade one, five years of job experience, mental health and non-addiction license. The criterion for not participating in this study was the lack of cooperation in responding to the questions. Six months was spent to collect the latest five years data of driving accidents from 2011 to 2016. A total of 323 truck and bus drivers in Tehran city and the suburbs, Iran were chosen. Among them, 112 were responsible for accidents (accident group) while 211 were not responsible for any accidents or involved in an accident in the last five years (non-accident group). A specially designed questionnaire was used to investigate the demographic information, medical drug consumption, medical backgrounds and history of accidents. RESULTS: The results revealed that compared with healthy subjects, the occurrence of accidents among people with diabetes (OR = 2.3, p = 0.001) and vision weakness (OR = 1.7, p = 0.020) was significantly higher, while that among people with cardiac (OR = 0.5, p = 0.002) and hypertension (OR = 0.9, p = 0.048) problems was remarkably lower. Moreover, consumption of Gemfibrozil (OR = 1.8, p = 0.010) and Glibenclamide (OR = 2.2, p = 0.002) drugs resulted in significantly higher incidence of accidents than those without. CONCLUSION Frequencies of illnesses like cardiovascular and hypertension were not higher in accident drivers than in non-accident drivers; but diabetes, vision weakness and consumption of Gemfibrozil and Glibenclamide lead to more traffic accidents.
Accidents, Traffic ; statistics & numerical data ; Adult ; Automobile Driving ; statistics & numerical data ; Cross-Sectional Studies ; Diabetes Mellitus ; epidemiology ; Drug Utilization ; statistics & numerical data ; Gemfibrozil ; administration & dosage ; Glyburide ; administration & dosage ; Humans ; Hypolipidemic Agents ; administration & dosage ; Incidence ; Iran ; epidemiology ; Male ; Middle Aged ; Surveys and Questionnaires ; Vision Disorders ; epidemiology

Serum levels of the pro-inflammatory apolipoprotein CIII (apoCIII) are increased in type-1 diabetic (T1D) patients and when β-cells are exposed to apoCIII they undergo apoptosis, which can be prevented by an antibody against apoCIII. We have previously investigated the BB rat, an animal model that develops a human-like T1D at the age of around 60 days, and found that apoCIII was also increased in sera from pre-diabetic rats and this promoted β-cell death. Lowering apoCIII with an oligonucleotide antisense during a phase of the pre-diabetic period prolonged the time to onset of T1D. In order to find other ways to lower apoCIII we in this study tested non-alcoholic red wine with medium and high concentrations of polyphenols and the lipid-lowering drug, fenofibrate, both reported to decrease the expression of apoCIII by activating peroxisome proliferator-activated receptors. Pre-diabetic BB-rats were treated orally for one month prior to the expected onset of diabetes with the two different wines or fenofibrate. None of the treatments prevented or prolonged the time to onset of diabetes and the expression of apoCIII was unaffected in this animal model for T1D. However, it must be emphasized that this does not exclude that other species can show a response to these substances.
Animals ; Apolipoprotein C-III ; Apoptosis ; Diabetes Mellitus* ; Fenofibrate* ; Humans ; Models, Animal ; Peroxisome Proliferator-Activated Receptors ; Polyphenols ; Rats ; Rats, Inbred BB* ; Wine*

Hypertriglyceridemia a major cause of acute pancreatitis, accounting for up to 10% of all cases. The pathophysiological mechanism of hypertriglyceridemia-induced acute pancreatitis (HTGP) is presumed to involve the hydrolysis of triglycerides by pancreatic lipase resulting in an excess of free fatty acids and elevated chylomicrons, which are thought to increase plasma viscosity and induce ischemia and inflammation in pancreatic tissue. Although the clinical course of HTGP is similar to other forms of acute pancreatitis, the clinical severity and associated complications are significantly higher in patients with HTGP. Therefore, an accurate diagnosis is essential for treatment and prevention of disease recurrence. At present, there are no approved guidelines for the management of HTGP. Different treatment modalities such as apheresis/plasmapheresis, insulin, heparin, fibric acids, and omega-3 fatty acids have been successfully implemented to reduce serum triglycerides. Following acute phase management, lifestyle modifications including dietary adjustments and drug therapy are important for the long-term management of HTGP and the prevention of relapse. Additional studies are required to produce generalized and efficient treatment guidelines for HTGP.
Chylomicrons ; Diagnosis ; Drug Therapy ; Fatty Acids, Nonesterified ; Fatty Acids, Omega-3 ; Fibric Acids ; Heparin ; Humans ; Hydrolysis ; Hypertriglyceridemia ; Inflammation ; Insulin ; Ischemia ; Life Style ; Lipase ; Pancreatitis* ; Plasma ; Recurrence ; Triglycerides ; Viscosity

Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome.
Apolipoprotein C-III ; Cardiovascular Diseases ; Diacylglycerol O-Acyltransferase ; Fatty Acids, Omega-3 ; Fibric Acids ; Hyperlipoproteinemia Type I ; Life Style ; Lipase ; Lipoprotein Lipase ; Lipoproteins ; Metabolism ; Mortality ; PPAR alpha ; Risk Factors ; Triglycerides

OBJECTIVE: To investigate the effects of sera from rats fed with tablets (HGT) on endoplasmic reticulum (ER) stress in a steatotic hepatocyte model of free fatty acids (FFAs)-induced nonalcoholic fatty liver disease (NAFLD) and explore the possible mechanism. METHODS: FFAs prepared by mixing oleic acid and palmitic acid at the ratio of 2:1. HepG2 cells were treated with the sera from rats fed with low-, moderate-or high-dose HGT (HGT sera) or sera of rats fed with fenofibrate (fenofibrate sera), followed by treatment with 1 mmol/L FFAs for 24 h to induce hepatic steatosis. Oil red O staining was used to observe the distribution of lipid droplets in the cells. The biochemical parameters including triglyceride (TG), lactated hydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured using a commercial kit. The morphological changes of the ER in the cells were observed using transmission electron microscopy. The protein/mRNA expressions of ER stress-related signal molecules including GRP78, PERK, p-PERK, ATF6, ATF4, CASPASE-12, CHOP, XBP-1, PKC, and p-PKC-δ were detected using Western blotting and/or quantitative real-time PCR (qRT-PCR). The changes in the protein expressions of GRP78, p-PERK, CASPASE-12 and CHOP were also detected in cells with transient transfection of PKC-δ siRNA for PKC-δ knockdown. RESULTS: Compared with the control cells, the cells treated with FFAs showed significantly increased levels of TG, AST, and ALT ( < 0.05). Compared with FFAs-treated cells, the cells pretreated with HGT sera or fenofibrate sera all showed significantly decreased TG, AST and ALT levels ( < 0.05), reduced accumulation of the lipid droplets ( < 0.05), and lowered protein or mRNA expression levels of GRP78, p-PERK, ATF6, ATF4, CHOP, CASPASE-12, XBP-1 and p-PKC-δ ( < 0.05). PKC-δ knockdown caused significantly reduced protein expressions of GRP78, p-PERK, CASPASE-12 and CHOP in the cells with FFA-induced hepatic steatosis ( < 0.001); treatment with high-dose HGT serum more significantly reduced the expressions of GRP78 ( < 0.001) and P-PERK ( < 0.01) in FFAs-induced cells with PKC-δ knockdown. CONCLUSIONS HGT serum can effectively prevent FFAs-induced steatosis in HepG2 cells by alleviating ER stress, in which PKC-δ may act as an important target.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Endoplasmic Reticulum ; ultrastructure ; Endoplasmic Reticulum Stress ; drug effects ; Fatty Acids, Nonesterified ; Fenofibrate ; administration & dosage ; Hep G2 Cells ; Humans ; Hypolipidemic Agents ; administration & dosage ; Microscopy, Electron, Transmission ; Non-alcoholic Fatty Liver Disease ; blood ; etiology ; prevention & control ; RNA, Messenger ; blood ; Rats ; Serum ; Tablets ; Triglycerides ; blood

OBJECTIVE: Previous studies have shown that fenofibrate therapy increases serum creatinine level and that there is a return of serum creatinine to baseline level after the discontinuation of the drug. We evaluated the effect of long-term fenofibrate therapy on creatinine levels and its reversibility in patients with hypertension and hypertriglyceridemia. METHODS: This retrospective study enrolled 54 hypertensive and hypertriglyceridemic patients taking fenofibrate for 3–6 years (Fenofibrate group) and 30 control patients with similar age, sex, follow-up duration, and creatinine levels (Control group). In 23 patients taking fenofibrate with low triglyceride level and/or with high creatinine levels, fenofibrate was discontinued, and creatinine levels were measured after 2 months. RESULTS: Creatinine levels increased in both the fenofibrate group (from 0.91±0.18 mg/dL to 1.09±0.23 mg/dL, p < 0.001) and the control group (from 0.94±0.16 mg/dL to 0.98±0.16 mg/dL, p=0.04) compared to baseline. However, the elevation was more pronounced in the fenofibrate group than in the control group (21.1±15.4% vs. 4.5±11.3%, p < 0.001). The discontinuation of fenofibrate lowered creatinine levels (from 1.39±0.32 mg/dL to 1.15±0.24 mg/dL, p < 0.001) which were still higher than pre-treatment levels (p=0.013). CONCLUSION: Long-term fenofibrate therapy significantly increased creatinine levels in hypertensive and hypertriglyceridemic patients. The effect of fenofibrate on creatinine level was partially reversible. This finding suggests that follow-up creatinine level is necessary with fenofibrate therapy.
Creatinine* ; Fenofibrate* ; Follow-Up Studies ; Humans ; Hypertension* ; Hypertriglyceridemia ; Retrospective Studies ; Triglycerides

BACKGROUND: Fibrates are widely used to treat hypertriglyceridemia, a risk factor for arteriosclerosis, but these compounds have been associated with renal dysfunction. This study aimed to investigate the effects of fibrates on renal function in relatively healthy adult subjects with no cardiovascular diseases. METHODS: This retrospective study included 558 outpatients who were prescribed 160 mg fenofibrate (fenofibrate group) or 10 mg atorvastatin (control group) between August 2007 and October 2015. The groups were randomly matched using propensity scores at a 1:1 ratio. Serum creatinine levels and estimated glomerular filtration rates before and after treatment were compared between the two groups. RESULTS: Patients in the fenofibrate group showed greater changes in serum creatinine levels than those in the control group (9.73%±9.83% versus −0.89%±7.37%, P<0.001). Furthermore, 55.1% of patients in the fenofibrate group, but only 6.1% of those in the control group, exhibited a serum creatinine level increase ≥0.1 mg/dL (P<0.001). The fenofibrate group showed significantly greater declines in the estimated glomerular filtration rate than the control group (−10.1%±9.48% versus 1.42%±9.42%, P<0.001). Moreover, 34.7% of the fenofibrate group, but only 4.1% of the control group, exhibited an estimated glomerular filtration rate decrease ≥10 mL/min·1.73 m² (P<0.001). CONCLUSION: Fenofibrate treatment resulted in increased serum creatinine levels and reduced estimated glomerular filtration rates in a primary care setting. Therefore, regular renal function monitoring should be considered essential during fibrate administration.
Adult ; Arteriosclerosis ; Atorvastatin Calcium ; Cardiovascular Diseases ; Creatinine ; Fenofibrate* ; Fibric Acids ; Glomerular Filtration Rate ; Humans ; Hypertriglyceridemia ; Outpatients ; Primary Health Care ; Propensity Score ; Retrospective Studies ; Risk Factors

OBJECTIVETo observe the efficacy of fenofibrate for hepatic steatosis in rats after severe burn.

METHODSTwenty-seven male SD rats were divided into sham injury group, burn group, and burn+ fenofibrate group according to the random number table, with 9 rats in each group. Rats in sham injury group were sham injured on the back by immersing in 37 ℃ warm water for 15 s and then remained without other treatment. Rats in burn group and burn+ fenofibrate group were inflicted with 30% total body surface area full-thickness scald (hereinafter referred to as burn) on the back by immersing in 98 ℃ hot water for 15 s, and then they were intraperitoneally injected with lactated Ringer's solution at post injury hour (PIH) 1. From PIH 24 to post injury day (PID) 8, rats in burn+ fenofibrate group were treated with fenofibrate in the dose of 80 mg·kg(-1)·d(-1), while those in burn group were treated with equivalent volume of saline. (1) Three rats of each group were respectively selected on PID 4, 6, and 8 for the collection of inferior vena caval blood samples. Serum content of total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), high density lipoprotein (HDL), and low density lipoprotein (LDL) was determined with fully automatic biochemical analyzer. Body mass of each rat was measured immediately after blood sampling, and then rats were sacrificed to collect liver tissue for weighing wet mass. The ratio of wet mass of liver tissue to body mass (liver index) was calculated. Meanwhile, gross observation of liver was performed. (2) One liver tissue sample was harvested from each rat at each time point to observe histopathologic changes with HE staining. One liver tissue slice of each rat at each time point was collected to evaluate degree of hepatic steatosis, and the number of rats in each group in each grade of hepatic steatosis was recorded. Measurement data were processed with analysis of variance of factorial design and SNK test, and enumeration data were processed with Kruskal-Wallis test and Nemenyi test.

RESULTS(1) The content of TC, TG, FFA, and HDL of rats in burn group on PID 4 was obviously different from that in sham injury group (with P values below 0.05). Compared with that in burn group, the content of TC, TG, and FFA of rats was significantly decreased (with P values below 0.05), while the content of HDL of rats was not obviously changed in burn+ fenofibrate group on PID 4 (P>0.05). There were no obvious differences in the content of LDL of rats among 3 groups on PID 4 (with P values above 0.05). The content of TC, TG, and HDL of rats in burn group on PID 6 was obviously different from that in sham injury group (with P values below 0.05). Compared with that in burn group, the content of TC and TG of rats was significantly decreased (with P values below 0.05), while the content of HDL of rats was significantly increased in burn+ fenofibrate group on PID 6 (P<0.05). There were no obvious differences in the content of FFA and LDL of rats among 3 groups on PID 6 (with P values above 0.05). The content of TC and HDL of rats in burn group on PID 8 was obviously different from that in sham injury group (with P values below 0.05). Compared with that in burn group, the content of TC of rats was significantly decreased (P<0.05), while the content of HDL of rats was not obviously changed in burn+ fenofibrate group on PID 8 (P>0.05). There were no obvious differences in content of TG, FFA, and LDL of rats among 3 groups on PID 8 (with P values above 0.05). (2) The texture of liver tissue of rats in burn+ fenofibrate group at each time point was tender and soft, without oil or fat on the section, which was close to the gross condition of liver of rats in sham injury group. Dark yellow plaque scattered on the surface of liver tissue of rats in burn group at each time point with oil and fat on the section, which was especially obvious on PID 6. There was no obvious difference in liver index of rats among 3 groups on PID 4 (F=1.63, P>0.05). On PID 6 and 8, the liver indexes of rats in sham injury group, burn group, and burn+ fenofibrate group were 0.0416±0.0016, 0.0533±0.0054, and 0.0370±0.0069; 0.0423±0.0034, 0.0624±0.0005, and 0.0444±0.0042 respectively. The liver indexes of rats in burn group on PID 6 and 8 were significantly higher than those in the other two groups (with P values below 0.05). There were no obvious differences in the liver indexes of rats between burn+ fenofibrate group and sham injury group on PID 6 and 8 (with P values above 0.05). (3) The liver tissue structure of rats in sham injury group was normal at each time point. Hepatic steatosis of rats in burn group at each time point appeared microvesicular and disperse, which was especially obvious on PID 6. Mild hepatic steatosis was observed in rats of burn+ fenofibrate group on PID 4, and then the structure of liver tissue gradually recovered to normal level from PID 6 on. The degree of hepatic steatosis of rats in sham injury group was 0 grade. One rat in I grade, 1 rat in II grade, and 7 rats in III grade were observed in hepatic steatosis of rats in burn group. Three rats in 0 grade, 4 rats in I grade, and 2 rats in II grade were observed in hepatic steatosis of rats in burn+ fenofibrate group. The degree of hepatic steatosis of rats in burn group was more severe than that in the other two groups (with χ(2) values respectively 56.25 and 162.44, P values below 0.05). The degree of hepatic steatosis of rats in burn+ fenofibrate group was more severe than that in sham injury group (χ(2)=27.51, P<0.05).

CONCLUSIONSFenofibrate can ameliorate the dyslipidemia of severely burned rat, and it can alleviate the degree of hepatic steatosis in certain degree.

Animals ; Burns ; pathology ; Cholesterol, HDL ; blood ; Cholesterol, LDL ; blood ; Dyslipidemias ; drug therapy ; Fatty Acids ; blood ; Fenofibrate ; pharmacology ; Liver ; pathology ; Liver Cirrhosis ; drug therapy ; Male ; Rats ; Rats, Sprague-Dawley ; Triglycerides ; blood

OBJECTIVETo investigate the role and mechanism of action of fibroblast growth factor-21 (FGF-21) in reducing triglyceride (TG) in the in vitro and in vivo models of nonalcoholic fatty liver disease (NAFLD).

METHODS(1) A mixture of free fatty acids was used to establish a model of steatosis in L02 cells, and the cells were treated with various concentrations of FGF-21 or fenofibrate. Twenty-four hours later, oil red O staining was performed to observe the degree of steatosis, and intracellular TG content was determined. RT-PCR and Western blot were applied to measure the mRNA and protein expression of sterol regulatory element-binding protein-1c (SREBP-1c). (2) High-fat diet was used to establish a mouse model of steatosis, and these mice were intraperitoneally injected with FGF-21 or fenofibrate. Eight weeks later, whole blood and liver samples were collected, and HE staining was performed to observe steatosis. Meanwhile, the serum levels of TG, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured, and TG content in the liver was also measured. One-way analysis of variance was used for comparison of data between multiple groups, and the least significant difference t-test was used for comparison between any two groups.

RESULTS(1) Compared with the control group, the model group showed significant steatosis, with significant increases in intracellular lipid droplets and TG content (t = -20.57, P < 0.01), while FGF-21 reduced the number of intracellular lipid droplets and TG content (F = 98.16, P < 0.01) in a dose-dependent manner. In addition, the model group had significantly increased mRNA and protein expression of SREBP-1c compared with the control group (t = -10.73 and -0.1006, both P < 0.01), while FGF-21 down-regulated the mRNA and protein expression of SREBP-1c (F = 161.35 and 36.72, both P < 0.01). (2) Compared with the mice in the control group, those in the model group showed significant steatosis and had significant increases in serum TG level and TG content in the liver (t = -18.84 and 15.71, both P < 0.01). FGF-21 relieved hepatic steatosis and reduced the serum TG level and TG content in the liver (t = 18.11 and 9.46, both P < 0.01). Moreover, FGF-21 reduced the serum levels of ALT and AST in NAFLD mice (t = 25.93 and 12.50, both P < 0.01).

CONCLUSIONFGF-21 can inhibit the synthesis of TG through suppressing the expression of SREBP-1c, which further confirms the potential therapeutic effect of FGF-21 in the treatment of NAFLD. This may provide new ideas for the treatment of NAFLD.

Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Cell Line ; Diet, High-Fat ; Disease Models, Animal ; Fenofibrate ; pharmacology ; Fibroblast Growth Factors ; pharmacology ; Mice ; Non-alcoholic Fatty Liver Disease ; blood ; drug therapy ; Sterol Regulatory Element Binding Protein 1 ; metabolism ; Triglycerides ; blood