Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet

Abstract

BackgroundOxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox.HypothesisWe hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction.Methods and ResultsWe examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP.ConclusionTaken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.

Downregulation of PGC-1αPrevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice

“…Importantly, global knockdown of PGC-1 α in mice fed a HF diet nullified the EET-A-mediated beneficial effects on mitochondrial fusion and ROS suppressing potential in visceral adipose tissue. Increasing HF intake has been shown to enhance free fatty acid generation and increase mitochondrial dysfunction and ROS [35–38]. Together, these results clearly indicate that a recruitment of PGC-1 α is crucial to the beneficial effects of the EET-agonist on mitochondrial function and on the reduction of fission and increase of fusion-associated processes in both adipose and hepatic tissues.…”

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

“…Also, a whole body of data indicate a central role for AMP-activated protein kinase (AMPK) in regulating insulin sensitivity, as sustained decreases in AMPK activity accompany insulin resistance, whereas AMPK activation increases insulin sensitivity. In HepG2 cells exposed to high glucose media, AMPK activity is decreased 108 ; and decrease in AMPK activity can be mediated by the inhibition of Sirtuin 1 (SIRT1) 109 , a redox-regulated NAD-dependent histone/protein deacetylase. Interestingly, heme-oxygenase 1 (HO-1), an endogenous anti-oxidant gene, can attenuate fructose-induced hepatic lipid accumulation and improve insulin sensitivity via the activation of SIRT1 gene expression 109,110 .…”

“…In HepG2 cells exposed to high glucose media, AMPK activity is decreased 108 ; and decrease in AMPK activity can be mediated by the inhibition of Sirtuin 1 (SIRT1) 109 , a redox-regulated NAD-dependent histone/protein deacetylase. Interestingly, heme-oxygenase 1 (HO-1), an endogenous anti-oxidant gene, can attenuate fructose-induced hepatic lipid accumulation and improve insulin sensitivity via the activation of SIRT1 gene expression 109,110 . Therefore, the identification of potent and specific AMPK activators may be beneficial for the prevention and treatment of metabolic syndrome–associated disorders.…”

Caffeine with Links to NAFLD and Accelerated Brain Aging

“…Vegetarians should carefully regulate phytosterol consumption over their lifespan to prevent interference with the beneficial effects of caffeine on cholesterol metabolism with relevance to NAFLD [37]. Excessive fructose consumption (fruit, fruit juices) should be avoided with fructose reported as a Sirt 1 inhibitor [162,163] with the induction of NAFLD. In the developing world, very low carbohydrate diets should be consumed to prevent the absorption of LPS into the blood stream with beneficial effects on magnesium deficiency and the induction of NAFLD [164].…”