Pemafibrate suppresses NLRP3 inflammasome activation in the liver and heart in a novel mouse model of steatohepatitis-related cardiomyopathy

Kanno, Kotaro; Koseki, Masahiro; Chang, Jiuyang; Saga, Ayami; Inui, Haruyuki; Okada, Takeshi; Tanaka, Katsunao; Asaji, Masumi; Zhu, Yinghong; Ide, Seiko; Saito, Shigeyoshi; Higo, Tomoaki; Okuzaki, Daisuke; Ohama, Tohru; Nishida, Makoto; Kamada, Y.; Ono, Masafumi; Saibara, Toshiji; Yamashita, Shizuya; Sakata, Yasushi

doi:10.1038/s41598-022-06542-8

Cited by 15 publications

(10 citation statements)

References 51 publications

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“…Interestingly, a recent transcriptomic analysis identified sex differences in IL-6 in male individuals with fatty liver disease [21], and our recent publication corroborates this finding [20]. Thus, we propose that innovative models, such as our DISH model, with reliable sex differences in the development of cardiomyopathy and NASH [20] and others [16 ▪▪ ] could provide the opportunity to discover elusive mechanisms critical to the development of NASH-associated cardiomyopathy.…”

Section: Sex Effects On Nonalcoholic Steatohepatitis and Cardiovascul...supporting

confidence: 70%

“…Hepatocytes, stellate, and immune cells secrete various bioactive factors that are linked to increased risk of cardiovascular disease. Specifically, IL-6-induced inflammation, a hallmark of NASH [13] and a well known driver of cardiovascular disease [14,15,16 && ], could explain the spectrum of biologic activities associated with the NASH-associated cardiomyopathy. Although the cells in the cardiovascular system, including endothelial cells and fibroblasts can produce IL-6 in response to IL-1b [17,18], it is likely that IL-6 expression is first noted in the liver [13] in the temporal evolution of NASH-related cardiomyopathy.…”

Section: Inflammation Connects Nonalcoholic Steatohepatitis and Cardi...mentioning

confidence: 99%

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Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk

Njoku¹,

Schilling²,

Finck

2022

Current Opinion in Lipidology

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Purpose of reviewNonalcoholic steatohepatitis (NASH) is a multisystem disease that affects not only the liver but also heart, pancreas, and kidney. We currently lack a comprehensive understanding of mechanisms responsible for the development of NASH-associated cardiomyopathy or the influence of sex on pathophysiology. There is a critical need to address these gaps in knowledge in order to accelerate translation of knowledge into clinical practice. Recent findingsNASH and cardiovascular disease share common risk factors such as chronic inflammation, hyperlipidemia, and insulin resistance. Early cardiac dysfunction in NASH that is independent of obesity or other cardiometabolic risk factors suggests roles for liver--heart crosstalk in disease pathogenesis. Inflammation is a driving force in the pathogenesis of NASH, and it is likely that 'spill over' of NASH inflammation contributes to the development of cardiomyopathy. However, molecular and cellular mechanisms that mediate NASH-associated cardiomyopathy remain unclear because of inherent limitations of experimental models. Even so, recent studies implicate inflammatory, metabolic, and physiologic mechanisms that enhance our understanding of NASH-associated cardiomyopathy and the role of liver-heart crosstalk. SummaryAn innovative, detailed, and mechanistic understanding of NASH-associated cardiomyopathy is relevant to public health and will be fundamental for the comprehensive care of these patients.

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Section: Sex Effects On Nonalcoholic Steatohepatitis and Cardiovascul...supporting

confidence: 70%

Section: Inflammation Connects Nonalcoholic Steatohepatitis and Cardi...mentioning

confidence: 99%

Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk

Njoku¹,

Schilling²,

Finck

2022

Current Opinion in Lipidology

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“…The effects of pemafibrate on NAFLD/NASH from a basic and clinical point of view are summarized in Table S2 In the NAFLD/NASH mouse model, pemafibrate reduced liver function test values and improved fatty liver, ballooning, inflammation, and fibrosis [ 84 , 85 , 86 , 87 ]. Regarding the mechanisms through which pemafibrate ameliorates NAFLD, the genes for β-oxidation in, and lipid transport out of the liver are enhanced and the energy metabolism is also upregulated via the induction of the UCP3 gene.…”

Section: Pemafibrate For Nafld Nash and Pbcmentioning

confidence: 99%

“…Regarding the mechanisms through which pemafibrate ameliorates NAFLD, the genes for β-oxidation in, and lipid transport out of the liver are enhanced and the energy metabolism is also upregulated via the induction of the UCP3 gene. Kanno et al [ 87 ] evaluated the effect of pemafibrate on hepatic steatosis in a novel mouse model of diet-induced steatohepatitis-related cardiomyopathy fed a high-fat, high-cholesterol, high-sucrose, and bile acid diet (NASH diet). Mice were fed an 8-week NASH diet with or without pemafibrate (0.1 mg/kg).…”

Section: Pemafibrate For Nafld Nash and Pbcmentioning

confidence: 99%

Novel Selective PPARα Modulator Pemafibrate for Dyslipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), and Atherosclerosis

Yamashita¹,

Rizzo

et al. 2023

Metabolites

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Statins, the intestinal cholesterol transporter inhibitor (ezetimibe), and PCSK9 inhibitors can reduce serum LDL-C levels, leading to a significant reduction in cardiovascular events. However, these events cannot be fully prevented even when maintaining very low LDL-C levels. Hypertriglyceridemia and reduced HDL-C are known as residual risk factors for ASCVD. Hypertriglyceridemia and/or low HDL-C can be treated with fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids. Fibrates were demonstrated to be PPARα agonists and can markedly lower serum TG levels, yet were reported to cause some adverse effects, including an increase in the liver enzyme and creatinine levels. Recent megatrials of fibrates have shown negative findings on the prevention of ASCVD, which were supposed to be due to their low selectivity and potency for binding to PPAR α. To overcome the off-target effects of fibrates, the concept of a selective PPARα modulator (SPPARMα) was proposed. Kowa Company, Ltd. (Tokyo, Japan), has developed pemafibrate (K-877). Compared with fenofibrate, pemafibrate showed more favorable effects on the reduction of TG and an increase in HDL-C. Fibrates worsened liver and kidney function test values, although pemafibrate showed a favorable effect on liver function test values and little effect on serum creatinine levels and eGFR. Minimal drug–drug interactions of pemafibrate with statins were observed. While most of the fibrates are mainly excreted from the kidney, pemafibrate is metabolized in the liver and excreted into the bile. It can be used safely even in patients with CKD, without a significant increase in blood concentration. In the megatrial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL-C and LDL-C levels, the incidence of cardiovascular events did not decrease among those receiving pemafibrate compared to those receiving the placebo; however, the incidence of nonalcoholic fatty liver disease was lower. Pemafibrate may be superior to conventional fibrates and applicable to CKD patients. This current review summarizes the recent findings on pemafibrate.

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“…The NLRP3 in ammasome was recently implicated in the pathogenesis of peritoneal injury and brosis 31,32 . Interestingly, pema brate reduces in ammasome activation and recovers brosis in the liver and heart 33,34 . However, the role of pema brate in regulating the NLRP3 in ammasome activity in PD-associated peritoneal brosis remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Selective Activation of PPARα Mitigates Peritoneal Inflammation and Fibrosis through NLRP3 Inflammasome Suppression and Inflammation Modulation

Shinkai,

Sasaki,

Tamura

et al. 2024

Preprint

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Peritoneal inflammation and fibrosis remain major challenges to the long-term maintenance of peritoneal dialysis. Pemafibrate, a selective peroxisome proliferator-activated receptor α (PPARα) modulator, has been implicated in the management of fibrosis-related disorders. We investigated whether pemafibrate ameliorates peritoneal inflammation and fibrosis and explored the underlying mechanisms in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO mice). MGO mice exhibited peritoneal fibrosis with increased expression of mesenchymal markers, transforming growth factor-β1 (TGF-β1), and substantial deposition of extracellular matrix (ECM) proteins. Additionally, MGO mice exhibited peritoneal inflammation as indicated by elevated tumor necrosis factor-α expression and macrophage infiltration in peritoneal tissue. These effects were mitigated by pemafibrate treatment, which also restored peritoneal membrane function. Furthermore, pemafibrate promoted anti-inflammatory macrophage polarization in both mice and THP-1 cells. In human peritoneal mesothelial cells (HPMCs), pemafibrate effectively inhibited interferon-γ-induced production of TGF-β1 and ECM while suppressing the proinflammatory cytokines nuclear factor-κB (NF-κB) and activator protein 1. The NF-κB inhibitory effect of pemafibrate involved stabilization of the NF-κB inhibitory protein IkBα. Notably, pemafibrate hindered activation of the NLR family pyrin domain containing 3/caspase-1 axis in interferon-γ-stimulated HPMCs. These findings suggest that pemafibrate ameliorates peritoneal inflammation and fibrosis, making it a promising candidate for peritoneal fibrosis therapy.

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Pemafibrate suppresses NLRP3 inflammasome activation in the liver and heart in a novel mouse model of steatohepatitis-related cardiomyopathy

Cited by 15 publications

References 51 publications

Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk

Mechanisms of nonalcoholic steatohepatitis-associated cardiomyopathy: key roles for liver–heart crosstalk

Novel Selective PPARα Modulator Pemafibrate for Dyslipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), and Atherosclerosis

Selective Activation of PPARα Mitigates Peritoneal Inflammation and Fibrosis through NLRP3 Inflammasome Suppression and Inflammation Modulation

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