Targeting PPARα in low ambient temperature exposure-induced cardiac dysfunction and remodeling

The present study demonstrates that the down-regulation of peroxisome proliferator-activated receptor-α (PPARα) results in chronic low ambient temperature (LT) exposure-induced cardiac dysfunction and remodeling, emphasizing the therapeutic potential of PPARα activation strategies (e.g. fenofibrate treatment) in LT-associated cardiac injury.

Effects of Various Conditions Related to Circadian Rhythm Disturbances on Plasma and Erythrocyte Lipids in Rats: A Peroxisomal Perspective

Background: It was aimed to investigate effects of various conditions known to cause circadian rhythm disturbances (i.e. calorie restriction, time-restricted feeding, constant light exposure) on various peroxisomal parameters and to compare those effects with that of fenofibrate, a PPARα agonist, in rats. Methods: Plasmalogens and some fatty acids in erythrocyte lysates were analyzed by GC. Peroxisomal metabolites including very long chain fatty acids as well as phytanic and pristanic acids in plasma were measured by GC-MS. Results: Unlike calorie restricted feeding, fenofibrate treatment yielded lower level of plasma phytanic acid concentration implying higher peroxisomal α-oxidation rate. However both calorie restriction and fenofibrate treatment exhibited lower plasmalogen, DHA and arachidonic acid contents of erythrocyte lysates. Conclusion: Shared effects of conditions associated with circadian rhythm disturbances and peroxisomal induction by fenofibrate on erythrocyte membrane lipids might indicate a link between them.

The Herbal Combination CPA4-1 Inhibits Changes in Retinal Capillaries and Reduction of Retinal Occludin in db/db Mice

Increased formation of advanced glycation end products (AGEs) plays an important role in the development of diabetic retinopathy (DR) via blood-retinal barrier (BRB) dysfunction, and reduction of AGEs has been suggested as a therapeutic target for DR. In this study, we examined whether CPA4-1, a herbal combination of Cinnamomi Ramulus and Paeoniae Radix, inhibits AGE formation. CPA4-1 and fenofibrate were tested to ameliorate changes in retinal capillaries and retinal occludin expression in db/db mice, a mouse model of obesity-induced type 2 diabetes. CPA4-1 (100 mg/kg) or fenofibrate (100 mg/kg) were orally administered once a day for 12 weeks. CPA4-1 (the half maximal inhibitory concentration, IC50 = 6.84 ± 0.08 μg/mL) showed approximately 11.44-fold higher inhibitory effect on AGE formation than that of aminoguanidine (AG, the inhibitor of AGEs, IC50 = 78.28 ± 4.24 μg/mL), as well as breaking effect on AGE-bovine serum albumin crosslinking with collagen (IC50 = 1.30 ± 0.37 μg/mL). CPA4-1 treatment ameliorated BRB leakage and tended to increase retinal occludin expression in db/db mice. CPA4-1 or fenofibrate treatment significantly reduced retinal acellular capillary formation in db/db mice. These findings suggested the potential of CPA4-1 as a therapeutic supplement for protection against retinal vascular permeability diseases.

Insulin Independence in Newly Diagnosed Type 1 Diabetes Patient following Fenofibrate Treatment

A 19-year-old girl was diagnosed with type 1 diabetes and showing polydipsia and polyuria. She was double autoantibody-positive and had a diabetes-prone tissue type. She was immediately started on insulin. Fenofibrate treatment (160 mg daily) was initiated seven days after diagnosis. The need for insulin quickly declined, and she took her last dose of insulin 19 days after the first dose of fenofibrate, having regained endogenous control of blood glucose concentrations. She has now been insulin independent for one year and 9 months. Unstimulated C-peptide has increased by 51% (317 to 479 pmol/l), and IA-2 autoantibody level has decreased by 65% (49 to 17 × 103 arbitrary units). Fenofibrate is a widely used drug for reducing triglyceride and cholesterol levels. Fenofibrate reverses and prevents autoimmune diabetes in nonobese diabetic (NOD) mice by increasing the amount of the sphingolipid sulfatide in islets. Sphingolipid metabolism is otherwise abnormal in the islets at diagnosis of type 1 diabetes. In conclusion, we describe a 19-year-old patient with classical newly diagnosed type 1 diabetes, which following fenofibrate treatment has been without insulin for 21 months.

Alterations in plasma triglycerides and ceramides: links with cardiac function in humans with type 2 diabetes

Cardiac dysfunction in T2D is associated with excessive FA uptake, oxidation, and generation of toxic lipid species by the heart. It is not known whether decreasing lipid delivery to the heart can effect improvement in cardiac function in humans with T2D. Thus, our objective was to test the hypothesis that lowering lipid delivery to the heart would result in evidence of decreased “lipotoxicity,” improved cardiac function, and salutary effects on plasma biomarkers of cardiovascular risk. Thus, we performed a double-blind randomized placebo-controlled parallel design study of the effects of 12 weeks of fenofibrate-induced lipid lowering on cardiac function, inflammation, and oxidation biomarkers, and on the ratio of two plasma ceramides, Cer d18:1 (4E) (1OH, 3OH)/24:0 and Cer d18:1 (4E) (1OH, 3OH)/16:0 (i.e., “C24:0/C16:0”), which is associated with decreased risk of cardiac dysfunction and heart failure. Fenofibrate lowered plasma TG and cholesterol but did not improve heart systolic or diastolic function. Fenofibrate treatment lowered the plasma C24:0/C16:0 ceramide ratio and minimally altered oxidative stress markers but did not alter measures of inflammation. Overall, plasma TG lowering correlated with improvement of cardiac relaxation (diastolic function) as measured by tissue Doppler-derived parameter e′. Moreover, lowering the plasma C24:0/C16:0 ceramide ratio was correlated with worse diastolic function. These findings indicate that fenofibrate treatment per se is not sufficient to effect changes in cardiac function; however, decreases in plasma TG may be linked to improved diastolic function. In contrast, decreases in plasma C24:0/C16:0 are linked with worsening cardiac function.

Pathogenic role of PPARα down-regulation in corneal nerve degeneration and impaired corneal sensitivity in diabetes

The purpose of this study was to investigate the protective role of Peroxisome Proliferator‐Activated Receptor‐alpha (PPARα) against diabetic keratopathy and corneal neuropathy. Corneal samples were obtained from diabetic and non-diabetic human donors. Streptozotocin-induced diabetic rats and mice were orally treated with PPARα agonist fenofibrate. As shown by immunohistochemistry and Western blotting, PPARα was down-regulated in the corneas of diabetic humans and rats. Immunostaining of β-III tubulin demonstrated that corneal nerve fiber metrics were decreased significantly in diabetic rats and mice, which was partially prevented by fenofibrate treatment. As evaluated using a Cochet-Bonnet aesthesiometer, corneal sensitivity was significantly decreased in diabetic mice, which was prevented by fenofibrate. <i>PPARα^-/-</i> mice displayed progressive decreases in the corneal nerve fiber density. Consistently, corneal sensitivity was decreased in <i>PPARα^-/-</i> mice relative to wild-type mice by nine months of age. Diabetic mice showed increased incidence of spontaneous corneal epithelial lesion, which was prevented by fenofibrate while exacerbated by PPARα knockout. Western blot analysis revealed significantly altered neurotrophic factor levels in diabetic rat corneas, which were partially restored by fenofibrate treatment. These results indicate that PPARα protects corneal nerve from degeneration induced by diabetes, and PPARα agonists have therapeutic potential in the treatment of diabetic keratopathy.

Pathogenic role of PPARα down-regulation in corneal nerve degeneration and impaired corneal sensitivity in diabetes

The purpose of this study was to investigate the protective role of Peroxisome Proliferator‐Activated Receptor‐alpha (PPARα) against diabetic keratopathy and corneal neuropathy. Corneal samples were obtained from diabetic and non-diabetic human donors. Streptozotocin-induced diabetic rats and mice were orally treated with PPARα agonist fenofibrate. As shown by immunohistochemistry and Western blotting, PPARα was down-regulated in the corneas of diabetic humans and rats. Immunostaining of β-III tubulin demonstrated that corneal nerve fiber metrics were decreased significantly in diabetic rats and mice, which was partially prevented by fenofibrate treatment. As evaluated using a Cochet-Bonnet aesthesiometer, corneal sensitivity was significantly decreased in diabetic mice, which was prevented by fenofibrate. <i>PPARα^-/-</i> mice displayed progressive decreases in the corneal nerve fiber density. Consistently, corneal sensitivity was decreased in <i>PPARα^-/-</i> mice relative to wild-type mice by nine months of age. Diabetic mice showed increased incidence of spontaneous corneal epithelial lesion, which was prevented by fenofibrate while exacerbated by PPARα knockout. Western blot analysis revealed significantly altered neurotrophic factor levels in diabetic rat corneas, which were partially restored by fenofibrate treatment. These results indicate that PPARα protects corneal nerve from degeneration induced by diabetes, and PPARα agonists have therapeutic potential in the treatment of diabetic keratopathy.