Ferroptosis Affects the Progression of Nonalcoholic Steatohepatitis via the Modulation of Lipid Peroxidation–Mediated Cell Death in Mice

Abstract

kr.Oxidative stress and its associated lipid peroxidation play a key role in nonalcoholic steatohepatitis (NASH). Ferroptosis is a recently recognized type of cell death characterized by an iron-dependent and lipid peroxidationemediated nonapoptotic cell death. We demonstrate the impact of ferroptosis on the progression of NASH induced by methionine/choline-deficient diet (MCD) feeding for 10 days. RSL-3 (a ferroptosis inducer) treatment showed decreased hepatic expression of glutathione peroxidase 4 (GPX4) and conversely increased 12/15-lipoxygenase, and apoptosis-inducing factor, indicating that ferroptosis plays a key role in NASH-related lipid peroxidation and its associated cell death. Consistently, levels of serum biochemical, hepatic steatosis, inflammation, and apoptosis in MCD-fed mice were exacerbated with RSL-3 treatment. However, MCD-fed mice treated with sodium selenite (a GPX4 activator) showed increase of hepatic GPX4, accompanied by reduced NASH severity. To chelate iron, deferoxamine mesylate salt was used. Administration of deferoxamine mesylate salt significantly reduced NASH severity and abolished the harmful effects of RSL-3 in MCD-fed mice. Finally, treatment with liproxstatin-1 (a ferroptosis inhibitor) repressed hepatic lipid peroxidation and its associated cell death, resulting in decreased NASH severity. Consistent with the in vivo findings, modulation of ferroptosis/GPX4 affected hepatocellular death in palmitic acideinduced in vitro NASH milieu. We conclude that GPX4 and its related ferroptosis might play a major role in the development of NASH.

Changes in Glutathione Content in Liver Diseases: An Update

“…Qi et al showed that ferroptosis leads to a diminished hepatic expression of GPx4: experiments performed on MCD-fed mice revealed a reduced GPx4 expression after RSL-3 (a ferroptosis inducer) administration. Moreover, a higher amount of apoptosis inducing factors were found in mice liver, indicating that ferroptosis plays a key role in NASH-associated cell death [90]. On the other hand, the administration of a ferroptosis inhibitor, Liproxstatin-1, reduces hepatic lipid peroxidation and cell death [90].…”

“…Moreover, a higher amount of apoptosis inducing factors were found in mice liver, indicating that ferroptosis plays a key role in NASH-associated cell death [90]. On the other hand, the administration of a ferroptosis inhibitor, Liproxstatin-1, reduces hepatic lipid peroxidation and cell death [90].…”

From overnutrition to liver injury: AMP-activated protein kinase in nonalcoholic fatty liver diseases

“…Knockout of Ripk3 ameliorates liver injury in these mice (135). Ferroptosis is a type of programmed cell death dependent on iron, producing lipid peroxidation-mediated cell death in NASH (136). Although it remains unclear whether pyroptosis, the highly inflammatory form of programmed cell death, occurs during NASH, the pyroptotic effector gasdermin D (GSDMD) and its pyroptosis-inducing fragment GSDMD-N are increased in human NASH.…”

Selenium: Tracing Another Essential Element of Ferroptotic Cell Death

“…The bona fide ferroptosis inhibitors ferrostatin-1 (Dixon et al, 2012) and liproxstatin-1 (Friedmann Angeli et al, 2014) exert their function as efficient radical trapping antioxidants (RTA), thereby preventing cellular autoxidation (Zilka et al, 2017). The protective effects of these compounds in mouse disease models include ischemia/reperfusion injuries of the kidney, liver, brain, heart, and intestine (Fang et al, 2019;Friedmann Angeli et al, 2014;Li et al, 2019aLi et al, , 2019bLinkermann et al, 2014;Tuo et al, 2017), acute renal failure (Friedmann Angeli et al, 2014), intracerebral hemorrhage (Li et al, 2017), neurodegeneration (Hambright et al, 2017), hemochromatosis (Wang et al, 2017), non-alcoholic steatohepatitis (Qi et al, 2020), and morphine tolerance (Chen et al, 2019), underlining the pathological role of lipid peroxidation and associated ferroptosis in numerous disease contexts. Vitamin E is perhaps the most efficient natural RTA found in organisms (Zilka et al, 2017).…”