Overexpression of PDE4D in mouse liver is sufficient to trigger NAFLD and hypertension in a CD36-TGF-β1 pathway: therapeutic role of roflumilast. (January 2022)

• Record Type: Journal Article
• Authors: Tao, Xiang; He, Haiqing; Peng, Jiangtong; Xu, Rui; Fu, Jing; Hu, Yuting; Li, Li; Yang, Xiaoyan; Feng, Xiuling; Zhang, Chao; Zhang, Lingmin; Yu, Xiyong; Shen, Ao; Huang, Kai; Fu, Qin
• Is Part Of: Pharmacological research. Volume 175(2022)
• Publication Date: 2022-01
• Subjects: AAV8 adeno-associated virus 8 -- Ach acetylcholine -- APOB apolipoprotein B -- cAMP cyclic adenosine monophosphate -- CCL2 C-C chemokine ligand 2 -- CD36 cluster of differentiation 36 -- CHO cholesterol -- COPD chronic obstructive pulmonary disease -- DBP diastolic blood pressure -- DGAT1 diacylglycerol acyltransferase 1 -- EVG Verhoeff's Van Gieson -- FA fatty acid -- FFA free fatty acid -- HDL-C high density lipoprotein cholesterol -- HE hematoxylin and eosin -- HFD high fat diet -- IL-6 interleukin6 -- IR insulin resistance -- LDL-C low density lipoprotein cholesterol -- NAFLD nonalcoholic fatty liver disease -- NASH nonalcoholic steatohepatitis -- NC normal chow -- NE norepinephrine -- PA palmitic acid -- PBAE poly (β-amino ester) -- PDE4 phosphodiesterase 4 -- PDGF platelet-derived growth factor -- Phe phenylephrine -- RAS renin-angiotensin system -- SBP systolic blood pressure -- SCD1 stearoyl-CoA desaturase 1 -- SIRT1 sirtuin1 -- SNP sodium nitroprusside -- SNS sympathetic nervous system -- SREBP1C sterol regulatory element-binding protein 1c -- TBG thyroxine binding globulin -- TG triglycerides -- TGF-β1 transforming growth factor-beta1 -- TNF-α tumor necrosis factor alpha -- VSMC vascular smooth muscle cell; PDE4D -- Nonalcoholic fatty liver -- Hypertension -- CD36 -- TGF-β1; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.106004
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Emerging evidence has shown that nonalcoholic fatty liver disease (NAFLD) may be both a consequence and a cause of hypertension. Recent studies have demonstrated that phosphodiesterase 4 (PDE4)-cAMP signaling represents a pathway relevant to the pathophysiology of metabolic disorders. This study aims to investigate the impact and the underlying mechanism of PDE4 in the pathogenesis of NAFLD and its associated hypertension. Here we demonstrated that high-fat-diet (HFD) fed mice developed NAFLD and hypertension, with an associated increase in hepatic PDE4D expression, which can be prevented and even reversed by PDE4 inhibitor roflumilast. Furthermore, we demonstrated that hepatic overexpression of PDE4D drove significant hepatic steatosis and elevation of blood pressure. Mechanistically, PDE4D activated fatty acid translocase CD36 signaling which facilitates hepatic lipid deposition, resulting in TGF-β1 production by hepatocytes and excessive TGF-β1 signaling in vessels and consequent hypertension. Specific silencing of TGF-β1 in hepatocytes by siRNA using poly (β-amino ester) nanoparticles significantly normalized hepatic PDE4D overexpression-activated TGF-β1 signaling in vessels and hypertension. Together, the conclusions indicated that PDE4D plays an important role in the pathogenesis of NAFLD and associated hypertension via activation of CD36-TGF-β1 signaling in the liver. PDE4 inhibitor such as roflumilast, which is clinically approved for chronic obstructive pulmonary disease (COPD) treatment, has the potential to be used as a preventive or therapeutic drug against NAFLD and associated hypertension in the future. Graphical Abstract: PDE4 inhibitor Roflumilast, a prescription medicine used in chronic obstructive pulmonary disease treatment, reverses fatty liver and associated hypertension through inhibiting hepatic PDE4D-CD36-TGF-β1 hyperactivation-enhanced TGF-β1 signaling in vessels. ga1