Abstract
This study was designed to investigate the antidiabetic and antihyperlipidemic effects and mechanisms of eburicoic acid (TRR); one component of Antrodia camphorata in vitro and in an animal model for 14 weeks. Expression levels of membrane glucose transporter type 4 (GLUT4); phospho-5′-adenosine monophosphate-activated protein kinase (AMPK)/total AMPK; and phospho-Akt/total Akt in insulin-resistant C2C12 myotube cells were significantly decreased by palmitate; and such decrease was prevented and restored by TRR at different concentrations. A group of control (CON) was on low-fat diet over a period of 14 weeks. Diabetic mice; after high-fat-diet (HFD) induction for 10 weeks; were randomly divided into six groups and were given once a day oral gavage doses of either TRR (at three dosage levels); fenofibrate (Feno) (at 0.25 g/kg body weight); metformin (Metf) (at 0.3 g/kg body weight); or vehicle (distilled water) (HF group) over a period of 4 weeks and still on HFD. Levels of glucose; triglyceride; free fatty acid (FFA); insulin; and leptin in blood were increased in 14-week HFD-fed mice as compared to the CON group; and the increases were prevented by TRR, Feno, or Metf as compared to the HF group. Moreover, HFD-induction displayed a decrease in circulating adiponectin levels, and the decrease was prevented by TRR, Feno, or Metf treatment. The overall effect of TRR is to decrease glucose and triglyceride levels and improved peripheral insulin sensitivity. Eburicoic acid, Feno, and Metf displayed both enhanced expression levels of phospho-AMPK and membrane expression levels of GLUT4 in the skeletal muscle of HFD-fed mice to facilitate glucose uptake with consequent enhanced hepatic expression levels of phospho-AMPK in the liver and phosphorylation of the transcription factor forkhead box protein O1 (FOXO1) but decreased messenger RNA (mRNA) of phosphenolpyruvate carboxykinase (PEPCK) to inhibit hepatic glucose production; resulting in lowered blood glucose levels. Moreover; TRR treatment increased hepatic expression levels of the peroxisome proliferator-activated receptor α (PPARα) to enhance fatty acid oxidation; but displayed a reduction in expressions of hepatic fatty acid synthase (FAS) but an increase in fatty acid oxidation PPARα coincident with a decrease in hepatic mRNA levels of sterol response element binding protein-1c (SREBP-1c); resulting in a decrease in blood triglycerides and amelioration of hepatic ballooning degeneration. Eburicoic acid-treated mice reduced adipose expression levels of lipogenic FAS and peroxisome proliferator-activated receptor γ (PPARγ) and led to decreased adipose lipid accumulation. The present findings demonstrated that TRR exhibits a beneficial therapeutic potential in the treatment of type 2 diabetes and hyperlipidemia.
Highlights
IntroductionType 2 diabetes has been proposed to display more than 90% of all diabetes mellitus patients [1]
The mode of action of TRR was investigated in a HFD-fed diabetic model. This present study examined whether TRR has its ability to translocate glucose transporter type 4 (GLUT4) to the cell membrane to facilitate membrane glucose uptake transport and enhance phospho-adenosine monophosphate protein kinase (AMPK) or not, and targeted genes were investigated including fatty acid oxidation peroxisome peroxisome proliferator-activated receptor α (PPARα) and lipogenic fatty acid synthase (FAS)
The expression levels of membrane GLUT4 and phospho-AMPK (p-AMPK)/total AMPK (t-AMPK) in the C2C12 myotubes were significantly decreased by palmitate, and such decrease was prevented and restored by 5, 10, and 25 μg/mL of TRR (Figure 2A–C)
Summary
Type 2 diabetes has been proposed to display more than 90% of all diabetes mellitus patients [1]. This disease is strongly associated with obesity and insulin resistance [2] and has revealed mechanisms of insulin resistance 1t.hIanttrtoadrugcetitotnhe either impairs in β-cell function or insulin insensitive action at adipose tissue, skeletal musclDei,aobretleisvmeerlltiitsussuisetshe[3c]o.re of multiple etiologies of chronic hyperglycemia. AsIstociisaterdawreithaonbedsityexapndeninssiuvlien rbeseicstaauncsee[2i]tangdrhoaws rsevoeanleldy moenchatnhisemsinofnienrsulhineraerstiswtaoncoed wall of the endemmthiuactsctealevr,geoerrtgltihrveeeereinttihsseCur ieinms n[p3aa]m.irsoimn uβ-mcellkfaunnechtiiornaio.r iTnhsuelinidinesnentisfiitievde accotiomnpatoaudnipdosseotifssuAe., sckienlentaalmomea are included as thAentrfoodlilaocwamipnhgorsa:tai(tSsynfr.uAinttirnodgiabcoindnaymoomf eAa).iscainpnreacmiooums eedaibcloe nfusnisgtuesdenodfemteicrptoeTnaoiwidasn,. Zhankuic acid A, BI,t isCr,areDa,ndanexdpenEs.ivTe bheecaussuebitmgreorwgseodnlywohnothlee inbnreorthheacrtownotoadinweadll o1f t0h-eheynddermoxicye-vγe-rdgroedenecalactone, 11-hydroxCyin-γna-mdoomduemcakalanechtiorani.eT,haeniddenetrifgieodsctoamtrpieounn-3dsβo-of Al.. HorOataufrracrteiocnesnt studies demonstraatneddatchtivaet iinngdreidffieenrtesnttoabneipmroavlemn oefdfiecilesn,tsienvdeirffaelrepnut raenicmoaml mpooduenlsdisncflruodmingAc.yctoatmoxpihc,oarnattia- including ergostatrieiannnfil-ma3maβlm-omatloodr[y4e,l]s,a,ndsdeevihmerymadlurnpoouemrbeoudcruoimlcaotpooircuynaadccstiivdfirtoy(m.TORAu2r.)rcea[cm5e,pn6ht]o,srtauatadnideinscdaluenmdcioninngstKerragteoddsitsathptraliteaniyn-3dβai-nfoftleird[e4ni]at, betic and antihyperldipehidydermoeibcuerficfoeicctsac[i7d].(TRRe2g) a[5r,d6]i,nagndstarnuccintuKredaiscptliavyitayntrideilaabteiotinc sahndipa(nStiAhyRp)e,rtlihpeidsekmeilceetfofenctosf eburicoic acid (TRR)[7(]F. Rigeguarredi1n)g, TstRru2c,tusruelapchtivuirtyenreilcataiocnidsh(ipTR(S3A)R, )o, rthdeeshkeyledtroonsouflepbhuuricroeinciacciadc(iTdR(RT)R(F4ig) uisreC13),, which is known asT2R42-,msueltphhyulreennieclaanciodst(TaRn3e),, aonr ddethhyedrreosiusldphifufreerneicncaecidin(TstRr4u)citsuCre31s, owfhTichR3isaknndowTnR4ase2x4i-sting more than –OHmCo1en5’tshCαyl1ep5no’essliatαinoonpsotoansniDet,ioarinnndgo.thnerDe irsidnigff.erence in structures of TR3 and TR4 existing more than –OH on
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