Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis

Abstract

Aberrant liver sirtuin 1 (SIRT1), a mammalian NAD þ-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease (ALD). However, the role of intestinal SIRT1 in ALD is presently unknown. This study investigated the involvement of intestine-specific SIRT1 in ethanol-induced liver dysfunction in mice. Ethanol feeding studies were performed on knockout mice with intestinal-specific SIRT1 deletion [SIRT1i knockout (KO)] and flox control [wild-type (WT)] mice with a chroniceplusbinge ethanol feeding protocol. After ethanol administration, hepatic inflammation and liver injury were substantially attenuated in the SIRT1iKO mice compared with the WT mice, suggesting that intestinal SIRT1 played a detrimental role in the ethanol-induced liver injury. Mechanistically, the hepatic protective effect of intestinal SIRT1 deficiency was attributable to ameliorated dysfunctional iron metabolism, increased hepatic glutathione contents, and attenuated lipid peroxidation, along with inhibition of a panel of genes implicated in the ferroptosis process in the livers of ethanol-fed mice. This study demonstrates that ablation of intestinal SIRT1 protected mice from the ethanol-induced inflammation and liver damage. The protective effects of intestinal SIRT1 deficiency are mediated, at least partially, by mitigating hepatic ferroptosis. Targeting intestinal SIRT1 or dampening hepatic ferroptosis signaling may have therapeutic potential for ALD in humans.

USP22 Protects Against Myocardial Ischemia–Reperfusion Injury via the SIRT1-p53/SLC7A11–Dependent Inhibition of Ferroptosis–Induced Cardiomyocyte Death

“…More importantly, depletion of SIRT1 has been reported to exacerbate I/R injury in aged livers (Chun et al, 2018). Furthermore, studies have shown that reduced intestinal expressions of SIRT1 can protect mice against alcohol-induced liver injury by reducing ferroptosis (Zhou et al, 2020). Based on the aforementioned literature, we proposed a hypothesis that USP22/SIRT1 axis may play pivotal roles in ferroptosis-induced cardiomyocyte death, and sought to define its roles in an animal model of MI/R and a cellular model of IR in cardiomyocytes, hoping to highlight a novel targeting approach to MI/R therapy.…”

Programmed cell death in alcohol-associated liver disease

“…21 Activated inflammasomes actlvate caspase 1/11, which mature GSDMD and pro-, IL-1β and pro-IL-18, resulting in release of DAMPs, IL-1β and IL-18 [30][31][32] Reactive hydroxyl radical by iron accumulation injures lipid membranes to induce lipid peroxidation and membrane instability, which can ultimately result in leakage of cellular material and cell death. [38][39][40][41][42][43] The role in or to immune cells Kupffer cells produce TNFα by LPS-TLR4 signal activation from leakage-gut. 5 Immune cells are activated by DAMPs released from necroptotic hepatocytes 5,[14][15][16] Autophagy plays a role of anti-inflammatory response and anti-steatosis via cannabinoid receptor 2 in Kupffer cells.…”

“…Accumulating evidence suggests that ferroptosis is a novel type of PCD in liver diseases including ALD. [39][40][41][42] Hepatic iron accumulation is causally linked with chronic alcohol consumption, and it also contributes to hepatic inflammation and development of HCC in ALD. 43,44 Iron accumulates in response to ethanol, at least in part due to increased expression of hepcidin, a 25 amino-acid peptide, primarily expressed in hepatocytes, that is secreted from the liver in response to increased H 2 O 2 concentrations in liver.…”

“…46 Another study demonstrated that intestinal specific deficiency of Sirtuin 1, a class III histone deacetylase that plays a critical, but controversial, role in intestinal inflammation and development of colitis, protected mice from the chronic plus binge-induced liver damage by attenuating ferroptosis. 40 In the future, ethanol-induced crosstalk between hepatocytes and immune cells in the regulation of ferroptosis is an essential issue that needs to be clarified and understood in the context of ALD.…”

The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

“…Dysregulation of ferroptosis is observed in a wide range of pathological conditions, including chronic pulmonary obstructive disease, intracerebral hemorrhage, degenerative diseases, acute kidney injury, and cancer 2,[9][10][11][12] . Accumulating evidence has addressed that blockage of ferroptosis can mitigate the development and progression of a number of liver diseases, including hemochromatosis, immune-mediated hepatitis, alcoholic steatohepatitis, and acute liver failure ( Fig.2 and Table 1) [13][14][15][16] . Nonetheless, in some circumstance, induction of ferroptosis may be beneficial for adjusting drug resistance and contributing to combined treatment regimens against hepatocellular carcinoma (HCC) [17][18][19] .…”