PPARα agonist fenofibrate attenuates iron-induced liver injury in mice by modulating the Sirt3 and β-catenin signaling

Abstract

Iron accumulation is frequently associated with chronic liver diseases. However, our knowledge on how iron contributes to the liver injury is limited. Aberrant Wnt/β-catenin signaling is a hallmark of several hepatic pathologies. We recently reported that peroxisome proliferator activated receptor alpha (PPARα) agonist, fenofibrate prevents iron induced oxidative stress and β-catenin signaling by chelating the iron. Sirtuin3 (Sirt3), a type of NAD+-dependent deacetylase that plays a critical role in metabolic regulation was found to prevent ischemia reperfusion injury by normalizing the Wnt/β-catenin pathway. In the present study, we explored if fenofibrate prevents iron induced liver injury by regulating the Sirt3 and β-catenin signaling. In-vitro and in-vivo iron treatment resulted in the downregulation of PPARα, Sirt3, active β-catenin and its downstream target gene c-Myc in the mouse liver. Pharmacological activation of Sirt3, both invitro and in vivo, by Honokiol (HK), a known activator of Sirt3, abrogated the inhibitory effect of iron overload on active β-catenin expression and prevented the iron induced upregulation of αSMA and TGFβ expression. Intrinsically, PPARα KO mice showed significant downregulation of hepatic Sirt3 levels. In addition, treatment of iron overload mice with PPARα agonist fenofibrate reduced hepatic iron accumulation and prevented iron induced downregulation of liver Sirt3 and active β-catenin, mitigating the progression of fibrosis. Thus, our results establish a novel link between hepatic iron and PPARα, Sirt3 and β-catenin signaling. Further exploration on the mechanisms by which fenofibrate ameliorates iron induced liver injury likely has significant therapeutic impact on iron associated chronic liver diseases.

Age-related effects of fenofibrate on the hepatic expression of sirtuin 1, sirtuin 3, and lipid metabolism-related genes

“…In contrast to our results, a study in Pparα knockout mice treated with 100 mg/kg FN for 6 weeks showed downregulation of hepatic Sirt3 expression, indicating the dependence of Sirt3 expression on PPARα in mouse liver (Mandala et al, 2021). Moreover, the FN treatment prevented iron-induced downregulation of hepatic Sirt3 in wild-type iron-overloaded mice (Mandala et al, 2021). Modulation of SIRT3 expression by FN appears to be variable under different experimental conditions.…”

“…Reports on hepatic Sirt3 expression upon FN treatment showed either no impact of the drug (approx. 400 mg/kg/day, 5 days) (Li & Wu, 2018) or prevention of iron overload-induced downregulation of Sirt3 (100 mg/kg, i.p., 6 weeks) (Mandala et al, 2021).…”

Nicotinamide Adenine Dinucleotide Precursor Suppresses Hepatocellular Cancer Progression in Mice

“…Previous studies confirmed that a decrease in NAD levels could affect the activities of NAD-dependent enzymes, such as the SIRT family proteins, and then promote the TGF-β signaling pathway [ 16 , 41 ]. Activating NAD-dependent enzymes or replenishing NAD by NAD precursors could attenuate TGF-β-related diseases [ 41 , 42 , 43 , 44 ]. In our study, we observed that TGF-β significantly promoted the migration and invasion of HepG2 cells in vitro, whereas NR supplementation was found to inhibit such effects.…”

Mitochondrial sirtuin 3 and various cell death modalities

“…On the other hand, iron overload can inhibit Sirt3 activity, leading to mitochondrial ROS accumulation and autophagy, which causes bone marrow damage (Zhou et al, 2021). Sirt3 activation plays a protective role in iron-overloaded liver cells via the Wnt/β-catenin pathway (Mandala et al, 2021). These findings shows that Sirt3 can control cell death mediated by iron overload.…”