Dual Peroxisome Proliferator-activated Receptor Research Articles

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.

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis

BackgroundPrimary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown.MethodsIn this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]).ResultsA total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P=0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (−1.93 vs. −1.15; difference, −0.78; 95% CI, −1.99 to 0.42; P=0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting.ConclusionsTreatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.)

Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARβ/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.

PPAR-alpha/gamma agonists, glucagon-like peptide-1 receptor agonists and metformin for non-alcoholic fatty liver disease: A network meta-analysis.

To undertake a network meta-analysis to compare the relative efficacy of a dual peroxisome proliferator-activated receptor (PPAR)α and PPARγ agonist, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and metformin in patients with non-alcoholic fatty liver disease (NAFLD). Electronic databases, including Embase®, PubMed® and The Cochrane Library, were searched systematically for eligible studies from inception to 20 July 2022. Randomized controlled trials (RCTs) that investigated aspartate aminotransferase, alanine aminotransferase (ALT) and triglyceride levels were considered for inclusion. Data were extracted using a standardized data collection table. A network meta-analysis was performed. Relative risk and 95% confidence interval were calculated for continuous data and I2 was used to assess the heterogeneity of studies. A total of 22 RCTs involving 1698 patients were eligible for inclusion in the analysis. Both direct analysis and indirect analysis showed that saroglitazar was significantly superior to GLP-1RAs in improving ALT levels. Metformin improved ALT levels, but the effect was not as good as saroglitazar. Saroglizatar was the most effective drug for improving NAFLD.INPLASY registration number: INPLASY202340066.

Saroglitazar, a Dual PPAR α/γ Agonist, Improves Atherogenic Dyslipidemia in Patients With Non-Cirrhotic Nonalcoholic Fatty Liver Disease: A Pooled Analysis

Cardiovascular disease is the leading cause of mortality in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effects of saroglitazar, a dual peroxisome proliferator-activated receptor α/γ agonist, on serum lipids in patients with NAFLD. A total of 221 patients (saroglitazar, 130; placebo, 91) with NAFLD from phase 2 and 3 double-blinded placebo-controlled randomized clinical trials were pooled to assess the impact of saroglitazar magnesium 4 mg on traditional lipids, very low density lipoprotein cholesterol (VLDL-C), and small dense LDL-C (sdLDL-C). Change from baseline in lipid parameters was performed by using analysis of covariance including treatment as fixed effect and baseline value, diabetes, hypertension, and statin use as covariates. Treatment with saroglitazar significantly improved total cholesterol (-17 mg/dL, 95% confidence interval [CI], -24 to 9; P < .001), triglyceride (-45 mg/dL, 95% CI, -60 to 31; P < .001), low-density lipoprotein cholesterol (-8 mg/dL, 95% CI, -15 to -1; P= .01), and VLDL-C (-8mg/dL, -14 to -3; P < .001). Saroglitazar improved serum lipids as early as 4-6 weeks of initiation of therapy, and these effects persisted for duration of therapy. Saroglitazar also improved the highly atherogenic sdLDL-C (-10 mg/dL, -17 to -2; P= .01). In subgroup analysis of patients with either diabetes or hypertension, saroglitazar significantly improved serum lipids. Saroglitazar improved the serum atherogenic lipoprotein profile in patients with NAFLD, irrespective of comorbid conditions and statin use. Saroglitazar has the potential to not only positively affect liver disease but also reduce cardiovascular risk in patients with NAFLD. (Trials registrations: CTRI 2015/10/006236, CTRI 173300410A0106, NCT03863574, and NCT03061721).

Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: Potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes

Experimental and clinical evidence implicate disrupted gut barrier integrity in provoking innate immune responses, specifically macrophages, towards the progression of non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptors (PPARs), a subset of the nuclear receptor superfamily, act to fine-tune several metabolic and inflammatory processes implicated in NASH. As such, the current study was carried out to decipher the potential role of dual PPAR α/δ activation using elafibranor (ELA) on ileal macrophage polarization (MP) and its likely impact on the liver in a NASH setting. To achieve this aim, an in vitro NASH model using fat-laden HepG2 cells was first used to validate the impact of ELA on hepatic fat accumulation. Afterwards, ELA was used in a combined model of dietary NASH and chronic colitis analogous to the clinical presentation of NASH parallel with intestinal barrier dysfunction. ELA mitigated fat accumulation in vitro as evidenced by Oil Red-O staining and curbed triglyceride levels. Additionally, ELA restored the expression of tight junctional proteins, claudin-1 and occludin, along with decreasing intestinal permeability and inflammation skewing ileal macrophages towards the M2 phenotype, as indicated by boosted arginase-1 (Arg1) and curtailed inducible nitric oxide synthase (iNOS) expression levels. These changes were aligned with a modulation in hepatic toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) along with ileal interleukin-10 (IL-10)/signal transducer and activator of transcription-3 (STAT3) axes. Overall, the present findings suggest that the dual PPAR α/δ agonist, ELA, may drive MP in the ileum towards the M2 phenotype improving intestinal integrity towards alleviating NASH.

Parsing the Role of PPARs in Macrophage Processes.

Cells are richly equipped with nuclear receptors, which act as ligand-regulated transcription factors. Peroxisome proliferator activated receptors (PPARs), members of the nuclear receptor family, have been extensively studied for their roles in development, differentiation, and homeostatic processes. In the recent past, there has been substantial interest in understanding and defining the functions of PPARs and their agonists in regulating innate and adaptive immune responses as well as their pharmacologic potential in combating acute and chronic inflammatory disease. In this review, we focus on emerging evidence of the potential roles of the PPAR subtypes in macrophage biology. We also discuss the roles of dual and pan PPAR agonists as modulators of immune cell function, microbial infection, and inflammatory diseases.

Efficacy of elafibranor in patients with liver abnormalities especially non-alcoholic steatohepatitis: a systematic review and meta-analysis.

Dyslipidemia is a very common medical disorder affecting nearly 33.5% of US adults over 20years of age. It represents the major risk factor for non-alcoholic fatty liver (NAFLD) and cardiovascular diseases, which is the most common cause of death worldwide. Elafibranor is a peroxisome proliferator-activated receptor (PPAR) alpha and delta dual agonist. A novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ), elafibranor, the agonist is an emerging therapy with promising hepatoprotective results. To estimate the efficacy of elafibranor in patients with liver abnormalities especially non-alcoholic steatohepatitis (NASH). We searched the following databases: PubMed, SCOPUS, Web of Science, and Cochrane Library for relevant clinical trials assessing the use of silymarin in patients with NAFLD. Risk of bias assessment was performed using Cochrane's risk of bias tool. We included the following outcomes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), HOMA-IR, total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C). We included four clinical trials. We found that elafibranor significantly reduced the levels of ALT {MD = -4.60 [-8.17, -1.04], (P = 0.01)}, GGT {MD = -16.57 [-26.59, -6.56], (P < 0.01)}, TC {MD = -0.37 [-0.66, -0.08], (P = 0.01)}, TG {MD = -0.37 [-0.51, -0.24], (P < 0.01)}, ALP {(MD = -14.45 [-18.99, -9.91], (P < 0.01)}, and LDL {MD = -0.20 [-0.33, -0.07], (P = 0.003)}. There was no significant difference regarding HOMA-IR {MD = -0.32 [-0.88, 0.24], (P = 0.26) and AST (P = 0.53). PPAR-alpha/delta dual agonist, elafibranor, is a promising drug that improves most metabolic parameters in dyslipidemic patients.

Both Elafibranor and Liraglutide Improve NAFLD / NASH but Affect Differentially the Hepatic Lipidome and Metabolome in a Diet-Induced Obese and Biopsy-Confirmed Mouse Model of NASH

Treatment of Nonalcoholic fatty liver disease (NAFLD) constitutes an unmet clinical need owing to the relatively limited efficacy of both novel and readily available metabolic medications, thus warranting pathobiological investigations on the mechanisms of single or combination regimens. In this context, our study aimed to assess and compare whether and how liraglutide, a glucagon-like peptide-1 receptor agonist, and elafibranor, a dual peroxisome proliferator-activated receptor alpha-delta agonist, may affect hepatic histology and metabolipidomic fingerprints in a model of advanced NAFLD. Male C57BL/6JRj mice with biopsy-confirmed hepatosteatosis and fibrosis induced by AMLN diet (40% fat with 20% trans-fat, 2% cholesterol and 22% fructose) were randomized to receive for 12 weeks: a) Liraglutide (0.4 mg/kg/d s.c.), b) Elafibranor (30 mg/kg/d p.o.), c) vehicle. Metabolic indices, liver function markers, liver pathology, and metabolomics/lipidomics were assessed at study completion. Both drugs markedly reduced body weight and fat percentage (p-value <0.001), and improved glucose tolerance and insulin sensitivity, as indicated by oral glucose and intraperitoneal insulin tolerance tests. Hepatic lipid content was downregulated under both treatments (p-value <0.001), especially under elafibranor, which also elevated liver weight in contrast with liraglutide (p-value vs liraglutide <0.001). NAFLD activity score (pre-to-post) and its histological components were substantially improved (mean difference ± standard error of mean: -1.4 ± 0.3 for liraglutide; -2.0 ± 0.2 for elafibranor), with elafibranor demonstrating a more robust anti-steatotic effect vs liralgutide (p-value <0.01) as well as anti-fibrotic effects (-0.5 ± 0.1). Liraglutide also limited the immunohistochemical expression of pro-inflammatory markers of Kupffer and hepatic stellate cell function (Galectin-3, Collagen type I alpha 1, and alpha-smooth muscle actin). In the omics analysis, elafibranor profoundly ameliorated the hepatic lipidome by diminishing the concentrations of glyceride species, increasing phospholipids and carnitine metabolites, and modifying key regulators of fatty acid oxidation, inflammation, and oxidative stress, including metabolites of methionine, glutathione, and pantothenate. Liraglutide significantly affected bile acid and carbohydrate metabolism by restoring the concentrations of metabolically beneficial primary and secondary bile acids, glycogen metabolism by-products, and pentoses, thus probably driving glycogen utilization-turnover and nucleic acid synthesis. Thus, liraglutide and elafibranor diverge in their mechanistic treatment of advanced NAFLD pathology, indicated by their robust but differential regulation of the hepatic metabolipidome. These findings support their combinatory therapeutic evaluation in future studies.

A Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of Saroglitazar in Patients With Primary Biliary Cholangitis.

INTRODUCTION:Patients with primary biliary cholangitis (PBC) without biochemical response to ursodeoxycholic acid (UDCA) are at increased risk of liver-related mortality. Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual PPAR agonistic properties (α/γ). There is a strong mechanistic rationale for studying saroglitazar in PBC because PPARα is a molecular target of fibrates that showed improvements in liver tests in patients with PBC.METHODS:In this 16-week, open-label, phase 3 study, 37 patients were screened across 3 clinical centers to enroll 7 patients. All patients received daily dose of saroglitazar 4 mg for 16 weeks in addition to their ongoing treatment with UDCA. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at week 16 as compared to baseline.RESULTS:Mean age of the study population was 51.1 ± 10.0 years, all patients were female of Mexican descent, and mean body mass index was 25.5± = 4.8 kg/m2. Six (85.7%) patients reported taking ursodiol at baseline and continued throughout the study with a mean daily dosage of 417 mg. Among these, the daily dosage of UDCA 500 mg in 4 and 250 mg in 2 subjects, respectively. The mean baseline ALP level was 230 ± 103 U/L. The primary efficacy endpoint, mean change (reduction) from baseline in ALP concentration at week 16 based on the modified intent-to-treat population was −94 ± 53 U/L (P = 0.003), corresponding to a reduction of 48 ± 23%. Treatment with saroglitazar 4 mg resulted in a rapid and sustained decrease of ALP levels at week 4 (−84 ± 47 U/L, P = 0.003). Six patients who completed the study achieved mean ALP reduction of at least 40% at week 4 and all subsequent visits.DISCUSSION:Although the study was terminated because of lack of enrollment, saroglitazar daily for 16 weeks resulted in rapid and sustained improvements in ALP with an acceptable safety profile in patients with PBC.

Design, synthesis, and biological evaluation of a novel dual peroxisome proliferator-activated receptor alpha/delta agonist for the treatment of diabetic kidney disease through anti-inflammatory mechanisms.

Diabetic kidney disease (DKD) is a major feature of the final stage of nearly all cause types of diabetes mellitus (DM). To date, few safe and effective drugs are available to treat. Peroxisome proliferator-activated receptors (PPARs), comprised of three members: PPAR-α, PPAR-δ and PPAR-γ, play a protective role in the DKD through glycemic control and lipid metabolism, whereas systemic activation of PPAR-γ causes serious side-effects in clinical trials. GFT505 is a dual PPAR-α/δ agonist, and the selectivity against PPAR-γ is still to be improved. Sulfuretin has been shown to suppress the expression of PPAR-γ and improve the pathogenesis of diabetic complications. In this study, by hybridizing the carboxylic acid of GFT505 and the parent nucleus of sulfuretin, we pioneeringly designed and synthetized a series of novel dual PPAR-α/δ agonists, expecting to provide a better benefit/risk ratio for PPARs. Of all the synthesized compounds, compound 12 was identified with highly activity on PPAR-α/δ and higher selectivity against PPAR-γ than that of GFT505 (EC50: hPPAR-α: 0.26μM vs.0.76μM; hPPAR-δ: 0.50μM vs.0.73μM; hPPAR-γ: 4.22μM vs.2.79μM). The molecular docking studies also depicted good binding affinity of compound 12 for PPAR-α and PPAR-δ compared to GFT505. Furthermore, compound 12 exhibited an evidently renoprotective effect on the DKD through inhibiting inflammatory process, which might at least partly via JNK/NF-κB pathways invivo and invitro. Overall, compound 12 hold therapeutic promise for DKD.

Effect of saroglitazar and pioglitazone on lipid parameters and glycemic profile in type II diabetes mellitus patients with dyslipidemia: An observational open-label study

Background: Diabetes mellitus when associated with dyslipidemia poses a different direction of management. For this subgroup of patients, we need stricter and different approach to improve treatment outcome and overall benefit. The introduction of dual peroxisome proliferator-activated receptors agonist has provided a new insight into the management of both diabetes and dyslipidemia. Aim and Objective: Hence, this study aimed to compare the effect of saroglitazar and pioglitazone on the lipid parameters and glycemic profile in patients of diabetes mellitus with dyslipidemia. Materials and Methods: Adult patients with diabetic mellitus with dyslipidemia fulfilling the inclusion criteria were included in the study. One group received saroglitazar (4 mg/day) and the other group received pioglitazone (15 mg/day). Lipid parameters; triglyceride (TG), low-density lipoprotein, high-density lipoprotein (HDL), and serum cholesterol levels and glycemic parameters; fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and glycosylated hemoglobin (HbA1C) were measured at baseline and month 3, 6, and 12. Results: Significant improvement seen in TG and HDL level at month 12 from baseline in both the treatment groups but saroglitazar was more effective than pioglitazone (P < 0.05). FPG, PPPG, and HbA1C were also reduced significantly from the baseline at the end of the study period (P < 0.05). Both the drugs were not associated with any sever adverse drug reactions. Conclusion: The current study showed that saroglitazar was more effective than pioglitazone in controlling lipid and glycemic parameters in diabetic patients with dyslipidemia.

Diabetes and Its Complications: Therapies Available, Anticipated and Aspired.

Worldwide, diabetes ranks among the ten leading causes of mortality. Prevalence of diabetes is growing rapidly in low and middle income countries. It is a progressive disease leading to serious co-morbidities, which results in increased cost of treatment and over-all health system of the country. Pathophysiological alterations in Type 2 Diabetes (T2D) progressed from a simple disturbance in the functioning of the pancreas to triumvirate to ominous octet to egregious eleven to dirty dozen model. Due to complex interplay of multiple hormones in T2D, there may be multifaceted approach in its management. The 'long-term secondary complications' in uncontrolled diabetes may affect almost every organ of the body, and finally may lead to multi-organ dysfunction. Available therapies are inconsistent in maintaining long term glycemic control and their long term use may be associated with adverse effects. There is need for newer drugs, not only for glycemic control but also for prevention or mitigation of secondary microvascular and macrovascular complications. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments. Several new agents like Glucagon Like Peptide - 1 (GLP-1) agonists, Dipeptidyl Peptidase IV (DPP-4) inhibitors, amylin analogues, Sodium-Glucose transport -2 (SGLT- 2) inhibitors and dual Peroxisome Proliferator-Activated Receptor (PPAR) agonists are available or will be available soon, thus extending the range of therapy for T2D, thereby preventing its long term complications. The article discusses the pathophysiology of diabetes along with its comorbidities, with a focus on existing and novel upcoming antidiabetic drugs which are under investigation. It also dives deep to deliberate upon the novel therapies that are in various stages of development. Adding new options with new mechanisms of action to the treatment armamentarium of diabetes may eventually help improve outcomes and reduce its economic burden.

An Observational Study of Reduction in Glycemic Parameters and Liver Stiffness by Saroglitazar 4 mg in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease.

BackgroundMetabolic abnormal conditions, such as diabetes and high triglycerides (TGs), are commonly associated with nonalcoholic fatty liver disease (NAFLD). Currently, there is no approved pharmacotherapy for NAFLD. Saroglitazar, the world’s first approved dual peroxisome proliferator-activated receptors (PPAR) α and γ agonist, was approved in India for the treatment of diabetic dyslipidemia. The objective of this study was to observe the safety and effectiveness of saroglitazar, 4 mg once daily, in reducing glycemic parameters and liver fibrosis in type 2 diabetes mellitus (T2DM) patients with NAFLD. MethodIn this prospective observational study, we enrolled 30 patients with T2DM and NAFLD (primarily detected by ultrasonography (USG) of the abdomen) who were treated with saroglitazar, 4 mg once daily, and the follow-up data were available for six months after saroglitazar treatment. During follow up, all patients were on stable antidiabetic and statin therapy. Liver stiffness was measured by FibroScan® (Echosens™ North America, Waltham, MA) elastography at baseline and at the six-month follow-up.ResultsAt the six-month follow-up after saroglitazar treatment, significant improvement was observed in glycemic parameters, liver stiffness on FibroScan, and serum transaminase levels. The serum TG levels were significantly reduced with saroglitazar. No major adverse event was reported.ConclusionIn this observational study of patients with T2DM and NAFLD, saroglitazar improved liver stiffness, as well as the glycemic and lipid parameters. A long-term randomized controlled clinical trial is required to further establish the safety and efficacy of saroglitazar in the treatment of T2DM and NAFLD.

Hepatoprotective effects of ZLY16, a dual peroxisome proliferator-activated receptor α/δ agonist, in rodent model of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD), a chronic progressive liver disease, covers a series of liver damage encompassing steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. However, there are no approved therapies for NAFLD. Herein, we characterize the pharmacological profile of ZLY16 ((E)-2-(4-(3-(2,3-dihydrobenzo[b]thiophen -5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid), a novel highly potent PPARα/δ agonist with relative higher potency on PPARγ. The chronic effects of ZLY16 on NASH development were evaluated in MCD-induced db/db mice. ZLY16 revealed decreased liver injury biomarkers, hepatic steatosis, inflammation, ballooning, and oxidative stress. Further mechanism researches suggested that ZLY16 inhibited liver inflammation and fibrosis by regulating gene expression including COLIA1, TIMP, TGFβ, TNFα, and IL6. Moreover, ZLY16 offers more favorable effects in decreasing liver TC and TG accumulation, blocking liver fibrosis and inflammation than GFT505, the most advanced candidate of PPARα/δ agonist for the treatment of NASH. These results indicate that ZLY16 is a highly potent PPARα/δ agonist that provides great protection against NASH development, and may be useful for the treatment of NAFLD/NASH.

Cardiovascular Risk and Safety Evaluation of a Dual Peroxisome Proliferator-Activated Receptor-Alpha/Gamma Agonist, Aleglitazar, in Patients With Type 2 Diabetes: A Meta-analysis.

This study evaluates the cardiovascular risk and safety of a dual peroxisome proliferator-activated receptor alpha and gamma (PPARα&γ), aleglitazar, for the management of type 2 diabetes mellitus. Studies were identified after a literature search in electronic databases and included in the meta-analysis according to eligibility criteria. Meta-analyses of mean differences in the changes from the baseline or odds ratios of selected indices between the aleglitazar- and the placebo/comparator-treated participants were performed. Seven studies {11,832 individuals; age 59.3 years [95% confidence interval (CI) 56.4-61.9]; body mass index 30.8 kg/m [95% CI 30.1-31.7]; sex, 54% males [44-64]} were included. In comparison with the placebo or pioglitazone, the aleglitazar treatment significantly improved %HbA1c, high-density lipoprotein-cholesterol (HDL-chol), and triglycerides. Aleglitazar also significantly decreased fasting plasma glucose and apolipoprotein B compared with the placebo. However, compared with the placebo or pioglitazone, aleglitazar significantly increased serum creatinine levels and significantly decreased the estimated glomerular filtration rate. In addition, the aleglitazar treatment was associated with a significantly increased body weight. Incidence of hypoglycemia, gastrointestinal hemorrhage, bone fractures, heart failure, cardiovascular death, and malignancy was higher in the aleglitazar group. Despite efficacy in glycemic and lipidic control, the aleglitazar treatment was associated with a poor safety profile.

A 3-week nonalcoholic steatohepatitis mouse model shows elafibranor benefits on hepatic inflammation and cell death.

The long duration of animal models represents a clear limitation to quickly evaluate the efficacy of drugs targeting nonalcoholic steatohepatitis (NASH). We, therefore, developed a rapid mouse model of liver inflammation (i.e., the mouse fed a high‐fat/high‐cholesterol diet, where cyclodextrin is co‐administered to favor hepatic cholesterol loading, liver inflammation, and NASH within 3 weeks), and evaluated the effects of the dual peroxisome proliferator‐activated receptor alpha/delta agonist elafibranor (ELA). C57BL6/J mice were fed a 60% high‐fat, 1.25% cholesterol, and 0.5% cholic acid diet with 2% cyclodextrin in drinking water (HFCC/CDX diet) for 3 weeks. After 1 week of the diet, mice were treated orally with vehicle or ELA 20 mg/kg q.d. for 2 weeks. Compared with vehicle, ELA markedly reduced liver lipids and nonalcoholic fatty liver disease activity scoring, through steatosis, inflammation, and fibrosis (all P < 0.01 vs. vehicle). Flow cytometry analysis showed that ELA significantly improved the HFCC/CDX diet‐induced liver inflammation by preventing the increase in total number of immune cells (CD45+), Kupffer cells, dendritic cells, and monocytes population, as well as the reduction in natural killer and natural killer T cells, and by blocking conversion of T cells in regulatory T cells. ELA did not alter pyroptosis (Gasdermin D), but significantly reduced necroptosis (cleaved RIP3) and apoptosis (cleaved caspase 3) in the liver. In conclusion, ELA showed strong benefits on NASH, including improvement in hepatic inflammation, necroptosis, and apoptosis in the 3‐week NASH mouse. This preclinical model will be useful to rapidly detect the effects of novel drugs targeting NASH.

Long-term outcomes of monascin - a novel dual peroxisome proliferator-activated receptor γ/nuclear factor-erythroid 2 related factor-2 agonist in experimental intracerebral hemorrhage.

Background:Hematoma is the chief culprit in brain injury following intracranial cerebral hemorrhage (ICH). Noninvasive hematoma clearance could be an option to prevent and alleviate early brain injury after ICH. Peroxisome proliferator-activated receptor γ (PPAR-γ) and nuclear factor-erythroid 2 related factor-2 (Nrf2) facilitate removal of hematoma in ICH. Monascin acts as the natural Nrf2 activator with PPAR-γ agonist, and the long-term effects of monascin following ICH have not been elucidated.Methods:ICH in rats was induced by stereotactic, intrastriatal injection of type IV collagenase. Monascin was administered twice daily by gastric perfusion for 14 days after ICH induction. Long-term neurological scores (T maze, Garcia scales, rotor rod test, and Morris water maze), hematoma volume, as well as iron overload around hematoma and brain atrophy were evaluated at 7, 14, and 28 days after ICH.Results:The results showed that monascin improved long-term neurological deficits, spatial memory performance, learning ability, and brain shrinkage after ICH. Monascin also reduced hematoma volume at 7 days and iron content at 7 and 14 days after ICH.Conclusion:PPAR γ and Nrf2 play a crucial role in hematoma clearance after ICH in rat. As a dual agonist of PPAR γ and Nrf2, monascin improved long-term outcomes by facilitating hematoma clearance, and by attenuating iron overload and brain atrophy after experimental ICH.

Dual peroxisome-proliferator-activated-receptor-α/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction.

Dual peroxisome proliferator-activated receptor (PPAR)α/γ agonists that were developed to target hyperlipidemia and hyperglycemia in type 2 diabetes patients, caused cardiac dysfunction or other adverse effects. We studied the mechanisms that underlie the cardiotoxic effects of a dual PPARα/γ agonist, tesaglitazar, in wild type and diabetic (leptin receptor deficient - db/db) mice. Mice treated with tesaglitazar-containing chow or high fat diet developed cardiac dysfunction despite lower plasma triglycerides and glucose levels. Expression of cardiac peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which promotes mitochondrial biogenesis, had the most profound reduction among various fatty acid metabolism genes. Furthermore, we observed increased acetylation of PGC1α, which suggests PGC1α inhibition and lowered sirtuin 1 (SIRT1) expression. This change was associated with lower mitochondrial abundance. Combined pharmacological activation of PPARα and PPARγ in C57BL/6 mice reproduced the reduction of PGC1α expression and mitochondrial abundance. Resveratrol-mediated SIRT1 activation attenuated tesaglitazar-induced cardiac dysfunction and corrected myocardial mitochondrial respiration in C57BL/6 and diabetic mice but not in cardiomyocyte-specific Sirt1-/- mice. Our data shows that drugs, which activate both PPARα and PPARγ lead to cardiac dysfunction associated with PGC1α suppression and lower mitochondrial abundance likely due to competition between these two transcription factors.

Discovery of a Novel Selective Dual Peroxisome Proliferator-Activated Receptor α/δ Agonist for the Treatment of Primary Biliary Cirrhosis.

A novel peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist 5c was developed with an EC50 of 8 nM for PPARα, 5 nM for PPARδ, and >300-fold selectivity against PPARγ (EC50 = 2939 nM), respectively. Further ADME and pharmacokinetic studies indicated 5c possessed distinguished in vitro and in vivo profiles. The excellent in vivo efficacy of compound 5c was demonstrated by the rat primary biliary cirrhosis (PBC) model.