A high-fat diet rich in corn oil induces cardiac fibrosis in rats by activating JAK2/STAT3 and subsequent activation of ANG II/TGF-1β/Smad3 pathway: The role of ROS and IL-6 trans-signaling
J Food Biochem.
Eid RA1, Alkhateeb MA2, El-Kott AF3,4, Eleawa SM5, Zaki MSA6,7, Alaboodi SA8, Salem Al-Shudiefat AA9, Aldera H2,10, Alnamar NM11, Alassiri M2,10, Khalil MA12.
1 Department of Clinica Pathology and Anatomy, College of Medicine, King Khalid University (KKU), Abha, Kingdom of Saudi Arabia.
2 Basic Medical Sciences (Physiology Section), College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Kingdom of Saudi Arabia.
3 Department of Biology, College of Science, King Khalid University (KKU), Abha, Kingdom of Saudi Arabia.
4 Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt.
5 Department of Applied Medical Sciences, College of Health Sciences, PAAET, Safat, Kuwait.
6 Department of Anatomy, College of Medicine, King Khalid University (KKU), Abha, Kingdom of Saudi Arabia.
7 Department of Histology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
8 Central laboratories, Huraymala General Hospital, Ministry of Health, Riyadh, Kingdom of Saudi Arabia.
9 Department of Medical Laboratory Sciences, the Hashemite University, Zarqa, Jordan.
10 King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia.
11 Khamis Mushait General Hospital, Ministry of Health, Abha, Kingdom of Saudi Arabia.
12 Department of Basic Medical Sciences, College of Medicine, King Fahid Medical City (KFMC), Riyadh, Kingdom of Saudi Arabia.
Year of Publication:
This study compared the effect of low-fat diet (LFD) and high-fat diet rich in corn oil (HFD-CO) on left ventricular (LV) fibrosis in rats and examined their effect of angiotensin II (ANG II), JAK/STAT, and TGF-1β/smad3 pathways. As compared to LFD which didn’t affect any of the measured parameters, HFD-CO-induced type 2 diabetes phenotype and increased LV collagen synthesis. Mechanistically, it increased LV levels of ROS, ANG II, ACE, IL-6, s-IL-6Rα, TGF-β1, Smad-3, and activities of JAK1/2 and STAT1/3. AG490, a JAK2 inhibitor, partially ameliorated these effect while Losartan, an AT1 inhibitor completely abolished collagen synthesis. However, with both treatments, levels of ANG II, IL-6, and s-IL-6Rα, and activity of JAK1/STAT3 remained high, all of which were normalized by co-administration of NAC or IL-6 neutralizing antibody. In conclusion: HFD-CO enhances LV collage synthesis by activation of JAK1/STAT3/ANG II/TGF-1β/smad3 pathway. PRACTICAL APPLICATIONS: We report that chronic consumption of a high-fat diet rich in corn oil (HFD-CO) induces diabetes mellitus phenotype 2 associated with left ventricular (LV) cardiac fibrosis in rats. The findings of this study show that HFD-CO, and through the increasing generation of ROS and IL-6 levels and shedding, could activate LV JAK1/2-STAT1/3 and renin-angiotensin system (RAS) signaling pathways, thus creating a positive feedback between the two which ultimately leads to activation of TGF-1β/Smad3 fibrotic pathway. Herein, we also report a beneficial effect of the antioxidant, NAC, or IL-6 neutralizing antibody in preventing such adverse effects of such HFD-CO. However, this presents a warning message to the current sudden increase in idiopathic cardiac disorders, especially with the big shift in our diets toward n-6 PUFA.