Insights into the Role of PPARβ/δ in NAFLD

Chen, Jiapeng; Montagner, Alexandra; Tan, Nguan Soon; Wahli, Walter

doi:10.3390/ijms19071893

Cited by 48 publications

(42 citation statements)

References 172 publications

(226 reference statements)

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“…The effectiveness of agonists for PPAR-α/δ has been confirmed in NASH patients as well[ 166 ]. Thus, the application of PPAR agonists, notably those for PPAR-β/δ isoforms, appears to be promising therapeutics for the treatment of NAFLD[ 167 ]. While the molecular mechanisms for how PPAR-β/δ controls insulin signaling are largely unknown, a stable interaction of PPAR-β/δ with nuclear T-cell protein tyrosine phosphatase 45 (TCPTP45) isoform has been demonstrated as the most upstream component that resolves the downregulation of insulin signaling[ 168 ].…”

Section: Non-alcoholic Fatty Liver Disease As a Representative Injurymentioning

confidence: 99%

Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease

Fujii

Homma

Kobayashi

et al. 2018

WJBC

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Reactive oxygen species (ROS) are produced during normal physiologic processes with the consumption of oxygen. While ROS play signaling roles, when they are produced in excess beyond normal antioxidative capacity this can cause pathogenic damage to cells. The majority of such oxidation occurs in polyunsaturated fatty acids and sulfhydryl group in proteins, resulting in lipid peroxidation and protein misfolding, respectively. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) is enhanced under conditions of oxidative stress and results in ER stress, which, together, leads to the malfunction of cellular homeostasis. Multiple types of defensive machinery are activated in unfolded protein response under ER stress to resolve this unfavorable situation. ER stress triggers the malfunction of protein secretion and is associated with a variety of pathogenic conditions including defective insulin secretion from pancreatic β-cells and accelerated lipid droplet formation in hepatocytes. Herein we use nonalcoholic fatty liver disease (NAFLD) as an illustration of such pathological liver conditions that result from ER stress in association with oxidative stress. Protecting the ER by eliminating excessive ROS via the administration of antioxidants or by enhancing lipid-metabolizing capacity via the activation of peroxisome proliferator-activated receptors represent promising therapeutics for NAFLD.

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Section: Non-alcoholic Fatty Liver Disease As a Representative Injurymentioning

confidence: 99%

Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease

Fujii

Homma

Kobayashi

et al. 2018

WJBC

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“…The results indicated that HWL‐088 has moderate agonistic activity on PPARδ, exhibiting high selectivity for PPARδ over PPARα and PPARγ. PPARδ activation produces multiple pharmacological effects, such as insulin sensibilization, adipocyte differentiation, anti‐inflammatory and lipid metabolism (Chen, Montagner, Tan, & Wahli, ; Lee et al, ; Luquet et al, ; Palomer et al, ). Moreover, the activation of PPARδ protects β‐cells from apoptosis (Daoudi et al, ), up‐regulating GLP‐1 receptor (Yang et al, ) and increasing mitochondrial function in β‐cells (Tang et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…These unique pharmacological effects might be attributed to the dual potencies of HWL‐088 by simultaneous activation of FFAR1 and PPARδ. Indeed, PPARδ play a key role in insulin sensibilization and lipid regulation, which could act synergistic effects with FFAR1 in glucose and lipid metabolism (Chen et al, ; Luquet et al, ; Palomer et al, ).…”

Section: Resultsmentioning

confidence: 99%

HWL‐088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice

Chen

Ren

Zhou

et al. 2020

British J Pharmacology

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Background and Purpose: The free fatty acid receptor 1 (FFAR1) plays an important role in glucose-stimulated insulin secretion making it an attractive antidiabetic target. This study characterizes the pharmacological profile of HWL-088(2-(2-fluoro-4-((2 0 -methyl-[1,1 0 -biphenyl]-3-yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the longterm effects of HWL-088 alone and in combination with metformin in diabetic mice.Experimental Approach: In vitro effects of HWL-088 on FFAR1 and PPARα/γ/δ were studied in cell-based assays. Glucose-dependent insulinotropic effects were evaluated in MIN6 cell line and in rats. Long-term effects on glucose and lipid metabolism were investigated in ob/ob mice.Key Results: HWL-088 is a highly potent FFAR1 agonist (EC 50 = 18.9 nM) with moderate PPARδ activity (EC 50 = 570.9 nM) and promotes glucose-dependent insulin secretion in vitro and in vivo. Long-term administration of HWL-088 exhibited better glucose control and plasma lipid profiles than those of another FFAR1 agonist, TAK-875, and synergistic improvements were observed when combined with metformin. Moreover, HWL-088 and combination therapy improved β-cell function by up-regulation of pancreas duodenum homeobox-1, reduced fat accumulation in adipose tissue and alleviated fatty liver in ob/ob mice.The effect of HWL-088 involves a reduction in hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid β-oxidation.Abbreviations: ACC1, acetyl-CoA carboxylase 1; ALT, alanine aminotransferase; ANGPTL3, angiopoietin-like 3; Apo C-II, apolipoprotein C-II; Apo C-III, apolipoprotein C-III; AS160, TBC1 domain family member 4; AST, aspartate transaminase; ATGL, adipose triglyceride lipase; BAT, brown adipose tissue; CKMB, creatine kinase-MB; CPT1α, carnitine palmitoyl transferase 1α; FAS, fatty acid synthetase; FFAR1, free fatty acid receptor 1; FLIPR, fluorometric imaging plate reader; G6Pase, glucose-6-phosphatase; GLP-1, glucagon-like peptide 1; GLUT4, glucose transporter 4; GSK3β, glycogen synthase kinase 3β; HbA1c, glycosylated haemoglobin; IP3, inositol triphosphate; LCAD, long-chain specific acyl-CoA dehydrogenase; LPL, lipoprotein lipase; OGTT, oral glucose tolerance test; PCNA, proliferating cell nuclear antigen; PDase, pyruvate dehydrogenase; PDX-1, pancreas duodenum homeobox-1; PEPCK, phosphoenol pyruvate carboxykinase; RT-PCR, reverse transcription-PCR; SAR, structure-activity relationship; SCD1, stearoyl-CoA desaturase 1; SD rats, Sprague-Dawley rats; SREBP-1c, sterol regulatory element-binding protein 1c; T2DM, type 2 diabetes mellitus; WAT, white adipose tissue.

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“…These salutary PPAR-δ functions in normal cells are thought to protect against metabolic-syndrome-related diseases, such as obesity, dyslipidemia, insulin resistance, hepatosteatosis, and atherosclerosis [ 44 , 45 ]. Therefore, highly selective synthetic PPAR-δ agonists (e.g., GW0742 [ 46 ], GW501516 [ 35 ]) were developed and tested clinically.…”

Section: Metabolic Regulation By Ppar-δmentioning

confidence: 99%

The Role of PPAR-δ in Metabolism, Inflammation, and Cancer: Many Characters of a Critical Transcription Factor

Liu

Colby

Zuo

et al. 2018

IJMS

133

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Peroxisome proliferator-activated receptor-delta (PPAR-δ), one of three members of the PPAR group in the nuclear receptor superfamily, is a ligand-activated transcription factor. PPAR-δ regulates important cellular metabolic functions that contribute to maintaining energy balance. PPAR-δ is especially important in regulating fatty acid uptake, transport, and β-oxidation as well as insulin secretion and sensitivity. These salutary PPAR-δ functions in normal cells are thought to protect against metabolic-syndrome-related diseases, such as obesity, dyslipidemia, insulin resistance/type 2 diabetes, hepatosteatosis, and atherosclerosis. Given the high clinical burden these diseases pose, highly selective synthetic activating ligands of PPAR-δ were developed as potential preventive/therapeutic agents. Some of these compounds showed some efficacy in clinical trials focused on metabolic-syndrome-related conditions. However, the clinical development of PPAR-δ agonists was halted because various lines of evidence demonstrated that cancer cells upregulated PPAR-δ expression/activity as a defense mechanism against nutritional deprivation and energy stresses, improving their survival and promoting cancer progression. This review discusses the complex relationship between PPAR-δ in health and disease and highlights our current knowledge regarding the different roles that PPAR-δ plays in metabolism, inflammation, and cancer.

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Insights into the Role of PPARβ/δ in NAFLD

Cited by 48 publications

References 172 publications

Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease

Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease

HWL‐088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice

The Role of PPAR-δ in Metabolism, Inflammation, and Cancer: Many Characters of a Critical Transcription Factor

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