pan-PPAR Agonist Research Articles

Chiglitazar attenuates high-fat diet-induced nonalcoholic fatty liver disease by modulating multiple pathways in mice

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide; however, effective intervention strategies for NAFLD are still unavailable. The present study sought to investigate the efficacy of chiglitazar, a pan-PPAR agonist, in protecting against NAFLD in mice and its underlying molecular mechanism. Male C57BL/6 J mice were fed a high-fat diet (HFD) for 8 weeks to generate NAFLD and the HFD was continued for an additional 10 weeks in the absence or presence of 5 mg/kg/d or 10 mg/kg/d chiglitazar by gavage. Chiglitazar significantly improved dyslipidemia and insulin resistance, ameliorated hepatic steatosis and reduced liver inflammation and oxidative stress in NAFLD mice. RNA-seq revealed that chiglitazar alleviated HFD-induced NAFLD in mice through multiple pathways, including fatty acid metabolism regulation, insulin signaling pathway, and AMPK signaling pathway. This study demonstrated the potential therapeutic effect of chiglitazar on NAFLD. Chiglitazar ameliorated NAFLD by modulating multiple pathways.

Bezafibrate mitigates oxidized-low density lipoprotein (ox-LDL)-induced the attachment of monocytes to endothelial cells: An implication in atherosclerosis.

Oxidized forms of low-density lipoproteins (ox-LDL)-associated endothelial dysfunction and subsequent monocyte adhesion play an important role in the development of atherosclerosis (AS). Bezafibrate (BEZ) is a peroxisome proliferator-activated receptor (pan-PPAR) agonist licensed as a hypolipidemic drug. However, the effects of BEZ on endothelial dysfunction are less reported. In this study, we aim to investigate the protective effects of BEZ on ox-LDL-challenged vascular endothelial cells to evaluate its potential value in treating AS. Human aortic endothelial cells (HAECs) and THP-1 cells were used to establish an In Vitro AS model. Cell Counting Kit-8 (CCK-8) assay, Real-time PCR, Western blot analysis, and Enzyme-linked immunosorbent assay (ELISA) were used to test the data. As expected, treatment with BEZ suppressed the expression of vascular endothelial growth factor A (VEGF-A), tissue factor (TF), Interleukin 12 (IL-12), tumor necrosis factor (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). BEZ was also found to inhibit ox-LDL-induced expression of the endothelial adhesion molecules vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HAECs. Correspondingly, BEZ prevented attachment of THP-1 monocytes to ox-LDL-incubated HAECs. Mechanically, BEZ was found to prevent NF-κB activation by reducing the levels of nuclear NF-κB p65 and inhibiting luciferase activity of NF-κB. Our study revealed the pharmacological function of BEZ in protecting endothelial dysfunction against ox-LDL, which may provide valuable insight for the clinical application of BEZ.

A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties

New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.

The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis

Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits.

MASLD/MASH and type 2 diabetes: Two sides of the same coin? From single PPAR to pan-PPAR agonists

Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very common conditions, share several disease pathways and clinical manifestations, and increasingly co-occur with disease progression. Insulin resistance is an upstream node in the biology of both conditions and triggers liver parenchymal injury, inflammation and fibrosis. Peroxisome proliferator-activated receptor (PPAR) nuclear transcription factors are master regulators of energy homeostasis − insulin signaling in liver, adipose and skeletal muscle tissue − and affect immune and fibrogenesis pathways. Among distinct yet overlapping effects, PPARα regulates lipid metabolism and energy expenditure, PPARβ/δ has anti-inflammatory effects and increases glucose uptake by skeletal muscle, while PPARγ improves insulin sensitivity and exerts direct antifibrotic effects on hepatic stellate cells. Together PPARs thus represent pharmacological targets across the entire biology of MASH. Single PPAR agonists are approved for hypertriglyceridemia (PPARα) and T2D (PPARγ), but these, as well as dual PPAR agonists, have shown mixed results as anti-MASH treatments in clinical trials. Agonists of all three PPAR isoforms have the potential to improve the full disease spectrum from insulin resistance to fibrosis, and correspondingly to improve cardiometabolic and hepatic health, as has been shown (phase II data) with the pan-PPAR agonist lanifibranor.

Benzopyran hydrazones with dual PPARα/γ or PPARα/δ agonism and an anti-inflammatory effect on human THP-1 macrophages

Peroxisome proliferator-activated receptors (PPARs) play a major role in regulating inflammatory processes, and dual or pan-PPAR agonists with PPARγ partial activation have been recognised to be useful to manage both metabolic syndrome and metabolic dysfunction-associated fatty liver disease (MAFLD). Previous works have demonstrated the capacity of 2-prenylated benzopyrans as PPAR ligands. Herein, we have replaced the isoprenoid bond by hydrazone, a highly attractive functional group in medicinal chemistry. In an attempt to discover novel and safety PPAR activators, we efficiently prepared benzopyran hydrazone/hydrazine derivatives containing benzothiazole (series 1) or 5-chloro-3-(trifluoromethyl)-2-pyridine moiety (series 2) with a 3- or 7-carbon side chain at the 2-position of the benzopyran nucleus. Benzopyran hydrazones 4 and 5 showed dual hPPARα/γ agonism, while hydrazone 14 exerted dual hPPARα/δ agonism. These three hydrazones greatly attenuated inflammatory markers such as IL-6 and MCP-1 on the THP-1 macrophages via NF-κB activation. Therefore, we have discovered novel hits (4, 5 and 14), containing a hydrazone framework with dual PPARα/γ or PPARα/δ partial agonism, depending on the length of the side chain. Benzopyran hydrazones emerge as potential lead compounds which could be useful for treating metabolic diseases.

Lanifibranor Reduces Inflammation and Improves Dyslipidemia in Lysosomal Acid Lipase-Deficient Mice

Background and AimsRecent studies showed that patients suffering from lysosomal acid lipase deficiency (LAL-D) benefit from enzyme replacement therapy (ERT), however, liver histolopathology improved in some but not all patients. We hypothesized that the pan-PPAR agonist lanifibranor may have beneficial effects on liver inflammation in LAL knockout (Lal-/-) mice based on its promising results in alleviating liver inflammation in patients with metabolic dysfunction-associated steatohepatitis. MethodsFemale Lal-/- mice were daily gavaged with lanifibranor or vehicle for 21 days. The effects of the treatment were assessed by measuring body and organ weights, plasma lipids and lipoproteins, as well as hematological parameters, followed by liver proteomics and metabolomics. ResultsLanifibranor treatment slightly altered organ weights without affecting the total body weight of Lal-/- mice. We observed major changes in the proteome, with multiple proteins related to lipid metabolism, peroxisomal, and mitochondrial activities being upregulated and inflammation-related proteins being downregulated in the livers of treated mice. Hepatic lipid levels and histology remained unaltered, whereas plasma triacylglycerol and total cholesterol levels were decreased and the lipoprotein profile of lanifibranor-treated Lal-/- mice improved. ConclusionsLanifibranor treatment positively affected liver inflammation and dyslipidemia in Lal-/- mice. These findings suggest the necessity of a further combined study of lanifibranor with ERT in Lal-/- mice to improve the phenotype. Moreover, there is a compelling rationale for conducting clinical trials to assess the efficacy of lanifibranor as a potential treatment option for LAL-D in humans.

Emerging therapeutic options for non-alcoholic fatty liver disease: A systematic review.

Non-alcoholic fatty liver disease (NAFLD) has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation. In the United States alone, annual medical costs are approximately 100 billion dollars. Unfortunately, there is no Federal Drug Administration (FDA)-approved medication for its treatment. However, various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD. It is valuable to have a compilation of the data available on their efficacy. To assess the efficacy of cyclophilin inhibitors, fibroblast growth factor 21 analogs (FGF21), and dual and pan peroxisome proliferator-activated receptor (PPAR) agonists for treating NAFLD. A comprehensive literature search using keywords including cyclophilin inhibitor, FGF agonist, pan-PPAR agonists, dual-PPAR agonist, NAFLD, non-alcoholic steatohepatitis, and fatty liver was conducted on October 29, 2022, in PubMed, EMBASE, Cochrane Library, Scopus and Web of Science. Animal and human research, case reports, and published articles in English from all countries with patients aged 18 and above were included. Only articles with a National Institutes of Health (NIH) Quality Assessment score of five or higher out of eight points were included. Articles that were narrative or systematic reviews, abstracts, not in English, focused on patients under 18 years old, did not measure outcomes of interest, were inaccessible, or had a low NIH Quality Assessment score were excluded. Each article was screened by two independent researchers evaluating relevance and quality. Resources were scored based on the NIH Quality Assessment Score; then, pertinent data was extracted in a spreadsheet and descriptively analyzed. Of the 681 records screened, 29 met the necessary criteria and were included in this review. These records included 12 human studies and 17 animal studies. Specifically, there were four studies on cyclophilin inhibitors, four on FGF agonists/analogs, eleven on pan-PPAR agonists, and ten on dual-PPAR agonists. Different investigational products were assessed: The most common cyclophilin inhibitor was NV556; FGF agonists and analogs was Efruxifermin; pan-PPAR agonists was Lanifibranor; and dual-PPAR agonists was Saroglitazar. All classes were found to be statistically efficacious for the treatment of NAFLD, with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan (P < 0.05). The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes, as well as good safety profiles (P < 0.05). We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.

844-P: Lanifibranor Improves Markers of Cardiometabolic Health in Patients with NASH and Type 2 Diabetes, Correlated with Responses in Adiponectin Levels

Background: Lanifibranor, a pan-PPAR agonist, has shown efficacy on liver histology and metabolic-immune markers of NASH in the phase 2b NATIVE study. PPAR signaling is involved in common pathways of NASH and type 2 diabetes (T2D). Adiponectin (ADP) is a pleiotropic adipokine which improves insulin resistance (IR), lipid metabolism, inflammation and fibrosis; low ADP levels are associated with risk for cardiovascular disease and NASH. Methods: NATIVE evaluated lanifibranor 800 and 1200 mg/d versus placebo in 247 patients with non-cirrhotic NASH for 24 weeks treatment. Of these 103 had T2D, 144 did not have T2D of whom 47 had prediabetes defined by fasting glucose levels (FGL) between 5.6 - 6.9 mmol/l. ADP serum levels, metabolic-immune and hepatic markers (glycemic control, IR, lipids, systemic inflammation) were measured at baseline (BL) and end of treatment (EOT). In each subgroup, we evaluated ADP at BL, ADP fold-change at EOT, and correlation between ADP change and response of markers. Results: ADP levels were lower in patients with T2D compared to those with pre-DM or normal glycemic control (NGC) (mean 4.6, 5.5, and 5.6 ug/ml, respectively). More patients with T2D had ADP below 5 mg/ml compared to pre-DM or NGC (65% vs 62/54%). In lanifibranor-treated group, ADP folds were similar in the 3 groups, with mean 4.3 fold increase by EOT, versus no increase in the placebo-treated group. In the pooled lanifibranor arms, increase in ADP correlated with improvements in glycemic control, IR, lipid metabolism, and systemic inflammation, consistently in the 3 groups, with higher improvements in patients with T2D and prediabetes compared to the NGC group. Conclusion: The pan-PPAR agonist lanifibranor significantly improves ADP levels and this improvement correlated with markers of cardiometabolic health in patients with T2D and prediabetes. Lanifibranor improves cardiovascular risk profile in patients with impaired glycemic control and NASH. Disclosure L.H.Griffel: Employee; Inventiva Pharma. S.Francque: None. M.F.Abdelmalek: Advisory Panel; Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Inventiva Pharma, Novo Nordisk, Merck &amp; Co., Inc., Sonic Incytes, NGM Biopharmaceuticals, Consultant; Hanmi Pharm. Co., Ltd., Research Support; Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Boehringer Ingelheim Inc., Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk, Poxel SA, DURECT Corporation, Enyo Pharma, Enanta, Genentech, Inc., Celgene, NGM Biopharmaceuticals, TARGET PharmaSolutions, Inc., Allergan. P.Huot-marchand: Employee; Inventiva Pharma. L.Dzen: Employee; Inventiva Pharma. M.Baudin: Employee; Inventiva Pharma. J.L.Junien: Consultant; Inventiva Pharma. P.Broqua: None. M.P.Cooreman: Employee; Inventiva Pharma.

Myelin Disruption, Neuroinflammation, and Oxidative Stress Induced by Sulfite in the Striatum of Rats Are Mitigated by the pan-PPAR agonist Bezafibrate.

Sulfite predominantly accumulates in the brain of patients with isolated sulfite oxidase (ISOD) and molybdenum cofactor (MoCD) deficiencies. Patients present with severe neurological symptoms and basal ganglia alterations, the pathophysiology of which is not fully established. Therapies are ineffective. To elucidate the pathomechanisms of ISOD and MoCD, we investigated the effects of intrastriatal administration of sulfite on myelin structure, neuroinflammation, and oxidative stress in rat striatum. Sulfite administration decreased FluoromyelinTM and myelin basic protein staining, suggesting myelin abnormalities. Sulfite also increased the staining of NG2, a protein marker of oligodendrocyte progenitor cells. In line with this, sulfite also reduced the viability of MO3.13 cells, which express oligodendroglial markers. Furthermore, sulfite altered the expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1), indicating neuroinflammation and redox homeostasis disturbances. Iba1 staining, another marker of neuroinflammation, was also increased by sulfite. These data suggest that myelin changes and neuroinflammation induced by sulfite contribute to the pathophysiology of ISOD and MoCD. Notably, post-treatment with bezafibrate (BEZ), a pan-PPAR agonist, mitigated alterations in myelin markers and Iba1 staining, and IL-1β, IL-6, iNOS and HO-1 expression in the striatum. MO3.13 cell viability decrease was further prevented. Moreover, pre-treatment with BEZ also attenuated some effects. These findings show the modulation of PPAR as a potential opportunity for therapeutic intervention in these disorders.

Targeting lipid-sensing nuclear receptors PPAR (α, γ, β/δ): HTVS and molecular docking/dynamics analysis of pharmacological ligands as potential pan-PPAR agonists.

The global prevalence of obesity-related systemic disorders, including non-alcoholic fatty liver disease (NAFLD), and cancers are rapidly rising. Several of these disorders involve peroxisome proliferator-activated receptors (PPARs) as one of the key cell signaling pathways. PPARs are nuclear receptors that play a central role in lipid metabolism and glucose homeostasis. They canactivate or suppress the genes responsible for inflammation, adipogenesis, and energy balance, making them promising therapeutic targets for treating metabolic disorders. In this study, an attempt has been made to screen novel PPAR pan-agonists from the ZINC database targeting the three PPAR family of receptors (α, γ, β/δ), using molecular docking and molecular dynamics (MD) simulations. The top scoring five ligands with strong binding affinity against all the three PPAR isoforms were eprosartan, canagliflozin, pralatrexate, sacubitril, olaparib. The ADMET analysis was performed to assess the pharmacokinetic profile of the top 5 molecules. On the basis of ADMET analysis, the top ligand was subjected to MD simulations, and compared with lanifibranor (reference PPAR pan-agonist). Comparatively, the top-scoring ligand showed better protein-ligand complex (PLC) stability with all the PPARs (α, γ, β/δ). When experimentally tested in in vitro cell culture model of NAFLD, eprosartan showed dose dependent decrease in lipid accumulation and oxidative damage. These outcomes suggest potential PPAR pan-agonist molecules for further experimental validation and pharmacological development, towards treatment of PPAR-mediated metabolic disorders.

WED-466 - The pan-PPAR agonist Lanifibranor improves increased portal pressure, endothelial dysfunction and liver histology in a rat model of early NAFLD

WED-466 - The pan-PPAR agonist Lanifibranor improves increased portal pressure, endothelial dysfunction and liver histology in a rat model of early NAFLD

WED-523 - Unraveling the individual contributions of the PPAR isotypes to the pan-PPAR agonist Lanifibranor-induced improvements of the vascular alterations and liver histology in a rat model of early NAFLD

WED-523 - Unraveling the individual contributions of the PPAR isotypes to the pan-PPAR agonist Lanifibranor-induced improvements of the vascular alterations and liver histology in a rat model of early NAFLD

THU-361 - The pan-PPAR agonist lanifibranor decreases portal pressure in models of both hepatic and prehepatic portal hypertension

THU-361 - The pan-PPAR agonist lanifibranor decreases portal pressure in models of both hepatic and prehepatic portal hypertension

The Synergistic Glucose-lowering Effects of Metformin and Bavachinin on Type II Diabetic Rats

Background: Diabetes is one of the most prevalent endocrine disorders in humans, and its first-line medication is metformin. Peroxisome proliferator-activated receptor gamma (PPAR–γ) agonists are the adjuncts to metformin. Bavachinin is a PPAR pan-agonist with fewer side effects than metformin" into PPAR–γ agonists. In this study, the synergistic effects of metformin and Bavachinin were investigated on type II diabetic rats. Methods: After four weeks of a high fat and glucose diet, type II diabetes was induced in 28 male Wistar rats, using injection of streptozotocin and nicotinamide. The animals were distributed into five groups of seven each: 1) Normal control (N), 2) Diabetic control (D), 3) Diabetic rats receiving metformin (DM), 4) Bavachinin (DB), and 5) Metformin plus Bavachinin (DMB). Oral glucose tolerance test (OGTT), fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of β-cell function (HOMA-β), homeostasis model assessment of insulin resistance (HOMA-IR), and insulin sensitivity index (ISI) were obtained. Results: The OGTT results in DM, DB, and DMB groups were significantly improved compared to that of D group. The FBG levels were significantly lower in DMB than in DB, DM, and D groups. The FINS levels of DMB were significantly less than those of DB, DM, and D groups. The HOMA-IR and HOMA-β were comparable between DMB and N groups. The ISI improved significantly in DMB compared to those in DM, DB, and D groups. Conclusion: Bavachinin may be used combined with metformin for the treatment of type II diabetes at lower doses of metformin, thus having fewer side effects.

Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity

Background and purposeSelective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPARα agonists on glucose metabolism and the adverse effects associated with selective PPARγ activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements. Experimental approachBP-2 was used in transactivation assays to evaluate its agonism to PPARα, PPARβ/δ and PPARγ. A parallel-plate flow chamber was employed to investigate its effect on TNFα-induced leukocyte-endothelium interactions. Flow cytometry and immunofluorescence were used to determine its effects on the expression of endothelial cell adhesion molecules (CAMs) and chemokines and p38-MAPK/NF-κB activation. PPARs/RXRα interactions were determined using a gene silencing approach. Analysis of its impact on metabolic abnormalities and inflammation was performed in ob/ob mice. Key resultsBP-2 displayed strong PPARα activity, with moderate and weak activity against PPARβ/δ and PPARγ, respectively. In vitro, BP-2 reduced TNFα-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX3CL1 expression, suppressed mononuclear cell arrest via PPARβ/δ-RXRα interactions and decreased p38-MAPK/NF-κB activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed T-lymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206. Conclusion and implicationsBP-2 emerges as a novel pan-PPAR lead candidate to normalize glycemia/triglyceridemia and minimize inflammation in metabolic disorders, likely preventing the development of further cardiovascular complications.

A change of paradigm in PBC: Pursuing normal alkaline phosphatase.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by a chronic and destructive lymphocytic cholangitis of the small bile duct, with variable risk of progression.1 Ursodeoxycholic acid (UDCA) is the first-line licensed disease-modifying treatment. Add-on therapy with obeticholic acid (OCA) is recommended for patients who do not respond to UDCA. Moreover, off-label therapy with the pan-PPAR agonist bezafibrate is recognised as an alternative and triple combination therapy -including UDCA, OCA, and fibrates- can normalise biochemical liver tests in difficult-to-treat PBC.

SAT119 - The pan-PPAR agonist lanifibranor improves markers of cardiometabolic health in patients with NASH independent of weight change

SAT119 - The pan-PPAR agonist lanifibranor improves markers of cardiometabolic health in patients with NASH independent of weight change

Disturbance of Mitochondrial Dynamics, Endoplasmic Reticulum-Mitochondria Crosstalk, Redox Homeostasis, and Inflammatory Response in the Brain of Glutaryl-CoA Dehydrogenase-Deficient Mice: Neuroprotective Effects of Bezafibrate.

Patients with glutaric aciduria type 1 (GA1), a neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) activity, commonly manifest acute encephalopathy associated with severe striatum degeneration and progressive cortical and striatal injury whose pathogenesis is still poorly known. We evaluated redox homeostasis, inflammatory response, mitochondrial biogenesis and dynamics, endoplasmic reticulum (ER)-mitochondria crosstalk, and ER stress in the brain of GCDH-deficient (Gcdh-/-) and wild-type (Gcdh+/+) mice fed a high Lys chow, which better mimics the human neuropathology mainly characterized by striatal lesions. Increased lipid peroxidation and altered antioxidant defenses, including decreased concentrations of reduced glutathione and increased activities of superoxide dismutase, catalase, and glutathione transferase, were observed in the striatum and cerebral cortex ofGcdh-/-mice. Augmented Iba-1 staining was also found in the dorsal striatum and neocortex, whereas the nuclear content of NF-κB was increased, and the cytosolic content of IκBα decreased in the striatum of the mutant animals, indicating a pro-inflammatory response. Noteworthy, in vivo treatment with the pan-PPAR agonist bezafibrate normalized these alterations. It was also observed that the ER-mitochondria crosstalk proteins VDAC1 and IP3R were reduced, whereas the ER stress protein DDIT3 was augmented in Gcdh-/- striatum, signaling disturbances of these processes. Finally, DRP1 content was elevated in the striatum ofGcdh-/-mice, indicating activated mitochondrial fission. We presume that some of these novel pathomechanisms may be involved in GA1 neuropathology and that bezafibrate should be tested as a potential adjuvant therapy for GA1.

Antioxidant system disturbances and mitochondrial dysfunction induced by 3-methyglutaric acid in rat heart are prevented by bezafibrate

Barth syndrome (BTHS) and dilated cardiomyopathy with ataxia syndrome (DCMA) are biochemically characterized by high levels of 3-methylglutaric acid (MGA) in the urine and plasma of affected patients. Although cardiolipin abnormalities have been observed in these disorders, their pathophysiology is not fully established. We evaluated the effects of MGA administration on redox homeostasis and mitochondrial function in heart, as well as on vascular reactivity in aorta of Wistar rats without cardiolipin genetic deficiency. Potential cardioprotective effects of a pretreatment with bezafibrate (BEZ), a pan-PPAR agonist that induces mitochondrial biogenesis, were also determined. Our findings showed that MGA induced lipid peroxidation, altered enzymatic and non-enzymatic antioxidant defenses and reduced respiratory chain function in rat heart. MGA also increased Drp1 and reduced MFN1 levels, suggesting mitochondrial fission induction. Moreover, MGA altered MAPK and Akt signaling pathways, and had a strong tendency to reduce Sirt1 and PGC-1α, indicative of mitochondrial biogenesis impairment. Aorta vascular reactivity was further altered by MGA. Additionally, BEZ mitigated most alterations on antioxidant defenses and mitochondrial quality control proteins provoked by MGA. However, vascular reactivity disturbances were not prevented. It may be presumed that oxidative stress, mitochondrial bioenergetics and control quality disturbances, and vascular reactivity impairment caused by MGA may be involved in the cardiac failure observed in BTHS and DCMA, and that BEZ should be considered as a pharmacological candidate for the treatment of these disorders.