Treating NASH by targeting peroxisome proliferator-activated receptors.

The pathophysiology of non-alcoholic steatohepatitis (NASH) encompasses a complex set of intra- and extrahepatic driving mechanisms, involving numerous metabolic, inflammatory, vascular and fibrogenic pathways. The peroxisome proliferator-activated receptors (PPARs) α, ß/δ and γ belong to the nuclear receptor family of ligand-activated transcription factors. Activated PPARs modulate target tissue transcriptomic profiles, enabling the body's adaptation to changing nutritional, metabolic and inflammatory environments. PPARs hence regulate several pathways involved in NASH pathogenesis. Whereas single PPAR agonists exert robust anti-NASH activity in several preclinical models, their clinical effects on histological endpoints of NASH resolution and fibrosis regression appear more modest. Simultaneous activation of several PPAR isotypes across different organs and within-organ cell types, resulting in pleiotropic actions, enhances the therapeutic potential of PPAR agonists as pharmacological agents for NASH and NASH-related hepatic and extrahepatic morbidity, with some compounds having already shown clinical efficacy on histological endpoints.

A Multiplex Molecular Cell-Based Sensor to Detect Ligands of PPARs: An Optimized Tool for Drug Discovery in Cyanobacteria.

Cyanobacteria produce a wealth of secondary metabolites. Since these organisms attach fatty acids into molecules in unprecedented ways, cyanobacteria can serve as a novel source for bioactive compounds acting as ligands for Peroxisome Proliferator-Activated Receptors (PPAR). PPARs (PPARα, PPARß/δ and PPARγ) are ligand-activated nuclear receptors, involved in the regulation of various metabolic and cellular processes, thus serving as potential drug targets for a variety of pathologies. Yet, given that PPARs' agonists can have pan-, dual- or isoform-specific action, some controversy has been raised over currently approved drugs and their side effects, highlighting the need for novel molecules. Here, we expand and validate a cell-based PPAR transactivation activity biosensor, and test it in a screening campaign to guide drug discovery. Biosensor upgrades included the use of different reporter genes to increase signal intensity and stability, a different promoter to modulate reporter gene expression, and multiplexing to improve efficiency. Sensor's limit of detection (LOD) ranged from 0.36-0.89 nM in uniplex and 0.89-1.35 nM in multiplex mode. In triplex mode, the sensor's feature screening, a total of 848 fractions of 96 cyanobacteria extracts were screened. Hits were confirmed in multiplex mode and in uniplex mode, yielding one strain detected to have action on PPARα and three strains to have dual action on PPARα and -ß.

Structural Biology-Based Exploration of Subtype-Selective Agonists for Peroxisome Proliferator-Activated Receptors.

Progress in understanding peroxisome proliferator-activated receptor (PPAR) subtypes as nuclear receptors that have pleiotropic effects on biological responses has enabled the exploration of new subtype-selective PPAR ligands. Such ligands are useful chemical biology/pharmacological tools to investigate the functions of PPARs and are also candidate drugs for the treatment of PPAR-mediated diseases, such as metabolic syndrome, inflammation and cancer. This review summarizes our medicinal chemistry research of more than 20 years on the design, synthesis, and pharmacological evaluation of subtype-selective PPAR agonists, which has been based on two working hypotheses, the ligand superfamily concept and the helix 12 (H12) holding induction concept. X-ray crystallographic analyses of our agonists complexed with each PPAR subtype validate our working hypotheses.

New dual peroxisome proliferator activated receptor agonist-Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence.

BACKGROUND: Saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) agonist, in clinical trials, has shown an improvement in lipid and glycemic parameters through the PPAR-α and γ agonist actions, respectively. It was granted marketing authorization in India in 2013 for diabetic dyslipidemia. This review was conducted to summarize the effects of Saroglitazar in patients with diabetic dyslipidemia in real world clinical studies conducted after marketing authorization in India. METHODS: In this review, we selected real world clinical studies of Saroglitazar published as manuscripts and abstracts presented at scientific conferences. In all these studies, patients with diabetic dyslipidemia were treated with Saroglitazar 4 mg once daily for at least 12 weeks and different lipid and glycemic parameters were measured at the baseline and end of the study. RESULTS: In 18 selected studies (5 published manuscripts and 13 abstracts), a total of 5824 patients with diabetic dyslipidemia were prescribed Saroglitazar 4 mg for a duration ranging from 12 to 58 weeks. Across all the studies, mean age of patients ranged from 49.6 to 59.1 years and the proportion of female patients ranged from 22% to 42%. Across all the studies, there was a consistent mean reduction in triglyceride levels (~ 45% to 62%), total cholesterol levels (~ 17% to 26%), non-high-density lipoprotein cholesterol levels (~ 21% to 36%), low-density lipoprotein cholesterol levels (~ 11% to 27%), and glycosylated hemoglobin levels (~ 0.7% to 1.6%) with an increase in mean high-density lipoprotein cholesterol levels (up to 9%) from baseline to end of the study. Saroglitazar also improved alanine aminotransferase levels and fatty liver (evaluated by FibroScan™) in non-alcoholic fatty liver disease patients with diabetic dyslipidemia. Body weight remained unchanged and no significant adverse events (AEs) were reported in the studies. CONCLUSION: Saroglitazar effectively improved lipid and glycemic parameters without significant AEs in patients with diabetic dyslipidemia in real-world clinical studies of up to 58 weeks duration.

Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common clinico-pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH. METHODS & RESULTS: HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1ß and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10µM concentration). Furthermore, these agents reversed PA-mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2-LX2 Coculture studies. In mice with choline-deficient high-fat diet-induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride-induced fibrosis model. CONCLUSIONS: Saroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone.

Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists.

Peroxisome proliferator-activated receptors (PPARs) are important drug targets for treatment of dyslipidemia, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and great efforts have been made to develop novel PPAR ligands. However, most existing PPAR ligands contain a carboxylic acid (CA) or thiazolidinedione (TZD) structure (acidic head group) that is essential for activity. We recently discovered non-CA/TZD class PPARα/δ partial agonists, which contain an acetamide moiety and adjacent methyl group, linked to a 1,2,4-oxadiazole ring ("fragment a"). We hypothesized that the acetamide structure might interact with the CA/TZD-binding pocket. To test this idea, we firstly replaced fragment a in one of our compounds with the α-alkoxy-CA structure often found in PPAR agonists. Secondly, we replaced the α-alkoxy-CA head group of several reported PPAR agonists with our acetamide-based fragment a. The agonistic activities of the synthesized hybrid compounds toward PPARs (PPARα, PPARγ and PPARδ) were evaluated by means of cell-based reporter gene assays. All the hybrid molecules showed PPAR-agonistic activities, but replacement of the α-alkoxy-CA head group altered the maximum efficacy and the subtype-specificity. The acetamide-based hybrid molecules showed partial agonism toward PPARα and PPARδ, whereas the α-alkoxy-CA-based molecules were generally selective for PPARα and PPARγ, with relatively high activation efficacies. Thus, the fragment replacement strategy appears promising for the development of novel acetamide-based PPARα/δ dual agonists.

Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice.

AIMS/HYPOTHESIS: Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. METHODS: Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db/db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. RESULTS: BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db/db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. CONCLUSIONS/INTERPRETATION: This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.

Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor ß/δ agonists with neuroprotective activity.

We report the pharmacophore of the peroxisome proliferator-activated receptor δ (PPARδ) agonist natural product phosphoiodyn A is the phosphonate core. Synthesis of simplified phosphonate esters 13 and 15 provide structurally novel, highly selective and potent PPARδ agonists (EC50=78 and 112 nM, respectively). Further, both compounds demonstrate significant neuroprotective activity in an in vitro cellular model indicating that phosphonates may be an effective novel scaffold for the design of therapeutics for the treatment of neurodegenerative disorders.

Structure-activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists.

The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that contribute to the regulation of lipid, glucose and cholesterol homeostases. They are considered as therapeutic targets for metabolic diseases such as dyslipidemia and type 2 diabetes mellitus. Various PPAR agonists have been developed, but most of them contain a carboxylic acid (CA) or thiazolidinedione (TZD) moiety, which is essential for the activity. However, we recently discovered non-CA/non-TZD class PPARα/δ dual agonists having an acetamide structure. Here, we describe structure-activity relationship (SAR) studies of these novel acetamide-based PPARα/δ dual agonists. The SAR studies revealed that the acetamide functionality and adjacent methyl group contribute greatly to the agonistic activity. Compound (S)-10 was the most potent PPARα/δ dual agonist among the compounds synthesized (PPARα EC50=17nM, PPARδ EC50=23nM).

Peroxisome Proliferator-Activated Receptor agonists and antagonists: an updated patent review (2020-2023).

INTRODUCTION: The search for novel compounds targeting Peroxisome Proliferator-Activated Receptors (PPARs) is currently ongoing, starting from the previous successfully identification of selective, dual or pan agonists. In last years, researchers' efforts are mainly paid to the discovery of PPARγ and δ modulators, both agonists and antagonists, selective or with a dual-multitarget profile. Some of these compounds are currently under clinical trials for the treatment of primary biliary cirrhosis, nonalcoholic fatty liver disease, hepatic, and renal diseases. AREAS COVERED: A critical analysis of patents deposited in the range 2020-2023 was carried out. The novel compounds discovered were classified as selective PPAR modulators, dual and multitarget PPAR agonists. The use of PPAR ligands in combination with other drugs was also discussed, together with novel therapeutic indications proposed for them. EXPERT OPINION: From the analysis of the patent literature, the current emerging landscape sees the necessity to obtain PPAR multitarget compounds, with a balanced potency on three subtypes and the ability to modulate different targets. This multitarget action holds great promise as a novel approach to complex disorders, as metabolic, inflammatory diseases, and cancer. The utility of PPAR ligands in the immunotherapy field also opens an innovative scenario, that could deserve further applications.

A pan-PPAR agonist E17241 ameliorates hyperglycemia and diabetic dyslipidemia in KKAy mice via up-regulating ABCA1 in islet, liver, and white adipose tissue.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disease. Peroxisome proliferator-activated receptors (PPARs) play crucial roles in regulating glucolipid metabolism. Previous studies showed that E17241 could ameliorate atherosclerosis and lower fasting blood glucose levels in ApoE-/- mice. In this work, we investigated the role of E17241 in glycolipid metabolism in diabetic KKAy mice. APPROACH AND RESULTS: We confirmed that E17241 is a powerful pan-PPAR agonist with a potent agonistic activity on PPARγ, a high activity on PPARα, and a moderate activity on PPARδ. E17241 also significantly increased the protein expression of ATP-binding cassette transporter 1 (ABCA1), a crucial downstream target gene for PPARs. E17241 clearly lowered plasma glucose levels, improved OGTT and ITT, decreased islet cholesterol content, improved ß-cell function, and promoted insulin secretion in KKAy mice. Moreover, E17241 could significantly lower plasma total cholesterol and triglyceride levels, reduce liver lipid deposition, and improve the adipocyte hypertrophy and the inflammatory response in epididymal white adipose tissue. Further mechanistic studies indicated that E17241 boosts cholesterol efflux and insulin secretion in an ABCA1 dependent manner. RNA-seq and qRT-PCR analysis demonstrated that E17241 induced different expression of PPAR target genes in liver and adipose tissue differently from the PPARγ agonist rosiglitazone. In addition, E17241 treatment was also demonstrated to have an exhilarating cardiorenal benefits. CONCLUSIONS: Our results demonstrate that E17241 regulates glucolipid metabolism in KKAy diabetic mice while having cardiorenal benefits without inducing weight gain. It is a promising drug candidate for the treatment of T2DM.

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

Background and Aims: Recent studies showed that patients suffering from lysosomal acid lipase deficiency (LAL-D) benefit from enzyme replacement therapy; however, liver histopathology improved in some but not all patients. We hypothesized that the pan-peroxisome proliferator-activated receptor 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. Methods: Female 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. Results: Lanifibranor 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. Conclusion: Lanifibranor treatment positively affected liver inflammation and dyslipidemia in Lal-/- mice. These findings suggest the necessity of a further combined study of lanifibranor with enzyme replacement therapy 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.

WY14643 Increases Herpesvirus Replication and Inhibits IFNß Production Independently of PPARα Expression.

Peroxisome proliferator activated receptor (PPAR) agonists are commonly used to treat metabolic disorders in humans because they regulate fatty acid oxidation and cholesterol metabolism. In addition to their roles in controlling metabolism, PPAR agonists also regulate inflammation and are immunosuppressive in models of autoimmunity. We aimed to test whether activation of PPARα with clinically relevant ligands could impact gammaherpesvirus infection using murine gammaherpesvirus-68 (MHV68, MuHV-4). We found that PPAR agonists WY14643 and fenofibrate increased herpesvirus replication in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPARα. We found that WY14643 suppressed production of type I interferon after MHV68 infection in vitro and in vivo. Taken together, our data indicate that caution should be employed when using PPARα agonists in immuno-metabolic studies, as they can have off-target effects on viral replication through the inhibition of type I interferon production. IMPORTANCE PPAR agonists are used clinically to treat both metabolic and inflammatory disorders. Because viruses are known to rewire host metabolism to their own benefit, the intersection of immunity, metabolism, and virology is an important research area. Our article is an important contribution to this field for two reasons. First, it shows a role for PPARα agonists in altering virus replication. Second, it shows that PPARα agonists can affect virus replication in a manner independent of their predicted target. This knowledge is valuable for anyone seeking to use PPARα agonists as a research tool.

Pharmacokinetics and Safety Evaluation of Single-Dose Saroglitazar Magnesium in Subjects with Hepatic Impairment.

Saroglitazar magnesium, a dual peroxisome proliferator-activated receptor agonist, is under evaluation for treating various liver conditions. While the pharmacokinetics (PK) of saroglitazar have been extensively studied in diverse preclinical models and healthy subjects, a comprehensive assessment of its PK behavior under conditions of hepatic impairment is lacking. In this Phase 1, open-label, parallel-group study, the PK of a single dose of 4-mg saroglitazar magnesium was investigated in subjects having varying degrees of hepatic impairment with and without portal hypertension compared with appropriately matched individuals having normal hepatic function. Treatment-emergent adverse events for safety were also evaluated. Thirty-two subjects were enrolled in the hepatic-impaired groups and 23 subjects in the normal hepatic function group. Mild and moderate hepatic impairment did not significantly affect the PK of saroglitazar, compared with normal hepatic function. Although severe hepatic impairment did not alter maximum observed plasma concentration and half-life; saroglitazar exposure (area under the plasma concentration-time curve from time 0 to infinity) increased 3-fold, while the clearance was 61% lower compared to the subjects with normal hepatic function. This may require close monitoring or dose adjustments in individuals with severe hepatic impairment. A single oral dose of saroglitazar magnesium 4 mg was found to be safe and well tolerated in subjects with varying degrees of hepatic function.

Saroglitazar for Nonalcoholic Fatty Liver Disease: A Single Centre Experience in 91 Patients.

Background: Saroglitazar is a novel, dual peroxisome proliferator-activated receptors-α/γ agonist and is being investigated for the treatment of nonalcoholic fatty liver disease (NAFLD). Patients and methods: Consecutive overweight (body mass index [BMI] >23 kg/m2) patients of NAFLD, diagnosed based on controlled attenuation parameter (CAP) >248 dB/m, and attending the outpatient department of a tertiary care centre in New Delhi, were enrolled. Patients with cirrhosis (liver stiffness measurement [LSM] >13.5 kPa) and those with concomitant liver disease due to other aetiologies (alcohol, viral, etc.) were excluded. All patients received saroglitazar 4 mg/day; in addition, they were advised to reduce weight and were counselled regarding diet and exercise. At 3-month follow-up, patients were categorized into those who were able to reduce ≥5% body weight and those who could n'ot, and both these groups were compared. Results: A total of 91 patients (median age 45 years [range 18-66 years]; 81% men) were included in the study. The median BMI was 29.3 kg/m2 (range 23.6-42.2 kg/m2). The baseline median (range) aspartate transaminase, alanine transaminase, gamma glutamyl transferase, LSM and CAP values were 40 IU/dL (range 22-144 IU/dL), 48 IU/dL (range 13-164 IU/dL), 42 IU/dL (range 4-171 IU/dL), 6.7 kPa (range 3.6-13.1 kPa), and 308 dB/m (range 249-400 dB/m). All patients tolerated saroglitazar well. At 3-month, 57 patients (63%) were able to reduce ≥5% weight, whereas in the remaining 34 patients (37%), the weight reduction was <5% from baseline. Transaminases values improved in both the groups; however, LSM and CAP values improved only in patients who reduced weight. Conclusion: In overweight patients with NAFLD, a 3-month therapy with saroglitazar is able to improve transaminases but not LSM and CAP values unless accompanied by weight reduction of at least 5%. Larger randomized controlled trials are needed to document the independent effect of saroglitazar in these patients.

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.

Fucoidan A2 from the Brown Seaweed Ascophyllum nodosum Lowers Lipid by Improving Reverse Cholesterol Transport in C57BL/6J Mice Fed a High-Fat Diet.

Reverse cholesterol transport (RCT) is a physiological process, in which excess peripheral cholesterol is transported to the liver and further excreted into the bile and then feces. Recently, fucoidans are reported to have a lipid-lowering effect. This study was designed to investigate whether fucoidan from the brown seaweed Ascophyllum nodosum lowers lipid by modulating RCT in C57BL/6J mice fed a high-fat diet. Our results indicated that fucoidan intervention significantly reduced plasma triglyceride, total cholesterol, and fat pad index and markedly increased high-density lipoprotein cholesterol in a dose-dependent manner. In the liver, fucoidan significantly increased the expression of peroxisome proliferator-activated receptor (PPAR)α, PPARγ, liver X receptor (LXR)ß, adenosine triphosphate (ATP) binding cassette (ABC)A1, ABCG8, low-density lipoprotein receptor (LDLR), scavenger receptor B type 1 (SR-B1), and cholesterol 7-α-hydroxylase A1 (CYP7A1) and decreased the triglyceride level and expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and PPARß but had no effect on LXRα, ABCG1, and ABCG5. In the small intestine, the fucoidan treatment significantly reduced the expression of Niemann-Pick C1-like 1 (NPC1L1) and improved ABCG5 and ABCG8. These results demonstrated that fucoidan can improve lipid transfer from plasma to the liver by activating SR-B1 and LDLR and inactivating PCSK9 and upregulate lipid metabolism by activating PPARα, LXRß, ABC transporters, and CYP7A1. In the small intestine, this fucoidan can decrease cholesterol absorption and increase cholesterol excretion by activating NPC1L1 and ABCG5 and ABCG8, respectively. In conclusion, fucoidan from A. nodosum may lower lipids by modulating RCT-related protein expression and can be explored as a potential compound for prevention or treatment of hyperlipidemia-related diseases.

Antidiabetic Drugs and Statins in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. Despite its high prevalence and rising incidence, there are currently no specific targeted pharmacotherapies approved by the Food and Drug Administration (FDA) for nonalcoholic steatohepatitis (NASH). Current therapies for patients with NAFLD include lifestyle modification. Vitamin E and pioglitazone are recommended for those confirmed to have NASH. However, there are concerns about the long-term safety of both pioglitazone and vitamin E in higher doses. Metformin is essential for managing the abnormal metabolic parameters in patients with NAFLD. Glucagon-like peptide-1 analogue, sodium-dependent glucose cotransporter inhibitors, and peroxisome proliferator-activated receptor agonists have shown benefits in improving metabolic parameters and reducing hepatic lipid accumulation and inflammation. However, the role of these antidiabetic agents in specifically reversing NASH needs to be established. Indeed, statins have been underprescribed in patients with NASH owing to fear of hepatotoxicity despite coronary artery disease being a common cause of death in patients with NAFLD. Statins reduce the risk of cardiovascular morbidity and mortality in patients with NASH and dyslipidemia. However, their use specifically for treatment of NASH needs further evaluation. Optimizing the control of risk factors remains the main strategy for treatment until targeted pharmacotherapies for NASH are available.

The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice.

Aim: Tafazzin knockdown (TazKD) in mice is widely used to create an experimental model of Barth syndrome (BTHS) that exhibits dilated cardiomyopathy and impaired exercise capacity. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that play essential roles as transcription factors in the regulation of carbohydrate, lipid, and protein metabolism. We hypothesized that the activation of PPAR signaling with PPAR agonist bezafibrate (BF) may ameliorate impaired cardiac and skeletal muscle function in TazKD mice. This study examined the effects of BF on cardiac function, exercise capacity, and metabolic status in the heart of TazKD mice. Additionally, we elucidated the impact of PPAR activation on molecular pathways in TazKD hearts. Methods: BF (0.05% w/w) was given to TazKD mice with rodent chow. Cardiac function in wild type-, TazKD-, and BF-treated TazKD mice was evaluated by echocardiography. Exercise capacity was evaluated by exercising mice on the treadmill until exhaustion. The impact of BF on metabolic pathways was evaluated by analyzing the total transcriptome of the heart by RNA sequencing. Results: The uptake of BF during a 4-month period at a clinically relevant dose effectively protected the cardiac left ventricular systolic function in TazKD mice. BF alone did not improve the exercise capacity however, in combination with everyday voluntary running on the running wheel BF significantly ameliorated the impaired exercise capacity in TazKD mice. Analysis of cardiac transcriptome revealed that BF upregulated PPAR downstream target genes involved in a wide spectrum of metabolic (energy and protein) pathways as well as chromatin modification and RNA processing. In addition, the Ostn gene, which encodes the metabolic hormone musclin, is highly induced in TazKD myocardium and human failing hearts, likely as a compensatory response to diminished bioenergetic homeostasis in cardiomyocytes. Conclusion: The PPAR agonist BF at a clinically relevant dose has the therapeutic potential to attenuate cardiac dysfunction, and possibly exercise intolerance in BTHS. The role of musclin in the failing heart should be further investigated.

Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure.

Recent progress in hearing loss research has provided strong evidence for the imbalance of cellular redox status and inflammation as common predominant mechanisms of damage affecting the organ of Corti including noise induced hearing loss. The discovery of a protective molecule acting on both mechanisms is challenging. The thiazolidinediones, a class of antidiabetic drugs including pioglitazone and rosiglitazone, have demonstrated diverse pleiotrophic effects in many tissues where they exhibit anti-inflammatory, anti-proliferative, tissue protective effects and regulators of redox balance acting as agonist of peroxisome proliferator-activated receptors (PPARs). They are members of the family of ligand regulated nuclear hormone receptors that are also expressed in several cochlear cell types, including the outer hair cells. In this study, we investigated the protective capacity of pioglitazone in a model of noise-induced hearing loss in Wistar rats and the molecular mechanisms underlying this protective effects. Specifically, we employed a formulation of pioglitazone in a biocompatible thermogel providing rapid, uniform and sustained inner ear drug delivery via transtympanic injection. Following noise exposure (120 dB, 10 kHz, 1 h), different time schedules of treatment were employed: we explored the efficacy of pioglitazone given immediately (1 h) or at delayed time points (24 and 48 h) after noise exposure and the time course and extent of hearing recovery were assessed. We found that pioglitazone was able to protect auditory function at the mid-high frequencies and to limit cell death in the cochlear basal/middle turn, damaged by noise exposure. Immunofluorescence and western blot analysis provided evidence that pioglitazone mediates both anti-inflammatory and anti-oxidant effects by decreasing NF-κB and IL-1ß expression in the cochlea and opposing the oxidative damage induced by noise insult. These results suggest that intratympanic pioglitazone can be considered a valid therapeutic strategy for attenuating noise-induced hearing loss and cochlear damage, reducing inflammatory signaling and restoring cochlear redox balance.