Hepatic progesterone receptor membrane component 1 attenuates ethanol-induced liver injury by reducing acetaldehyde production and oxidative stress

Abstract

Alcohol-associated liver disease (ALD) is caused by excessive abuse of alcohol. One of the most representative causes of ALD is the action of acetaldehyde. Acetaldehyde is toxic material produced when alcohol is metabolized through some enzymes, and it causes endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and tissue injury. In this study, we assessed the relevance between Progesterone receptor membrane component 1 (PGRMC1) and ALD because PGRMC1 is expressed in the endoplasmic reticulum and mitochondria in the liver. Using the chronic and binge alcohol feeding models, we assessed acetaldehyde level, liver damage, alcohol-degrading enzymes, and ER stress. Compared with wild-type (WT) mice, ethanol-fed Pgrmc1 knockout (KO) mice had higher levels of ALT and alcohol-degrading enzymes, and Pgrmc1 KO mice had high serum acetaldehyde and ER stress levels compared with WT mice in control and ethanol feeding. Loss of Pgrmc1 increased acetaldehyde production through increased expression of alcohol dehydrogenase and catalase, which led to increased ER stress and suggested that cell death was promoted. In conclusion, it has been proposed that the loss of PGRMC1 could promote ALD and cause liver damage in alcohol-abusing humans.

Progesterone Receptor Membrane Component 1 Regulates Cellular Stress Responses and Inflammatory Pathways in Chronic Neuroinflammatory Conditions

“…Based on this evidence, we hypothesized that reduced PGRMC1 levels would be vulnerable to neuroinflammation, because the Pgrmc1 KO mice exhibited higher levels of inflammationrelated factors, such as nuclear factor (NF)-κB, ER stress, and apoptosis, compared to those of the WT mice. These findings will be reminiscent of our earlier observations in our alcoholic liver disease study [23]. In an early report concerning neurological diseases, PGRMC1 induced proliferation of neural progenitor cells, regulated neurogenesis and synapse remodeling [34,35], inhibited TNF-α induction of gene expression in neural cells [36], and had neuroprotective effects in neonatal hypoxic-ischemic brain injury [37], related to brain-derived neurotrophic factor (BDNF) signaling [38,39].…”

“…In a previous study, we showed that Pgrmc1 KO mice had higher ER stress-related protein markers in the liver compared to those of WT mice [23]. Moreover, several reports have suggested that inflammatory cytokines can induce ER stress, which can activate the unfolded protein response (UPR) [46,47].…”

“…Progesterone receptor membrane component 1 (PGRMC1) is expressed in various tissues, including the liver, uterus, ovary, heart, and mammary gland, and in breast cancer [23][24][25][26][27]. It is located in the endomembranes, including the endoplasmic reticulum (ER), plasma membrane, nucleus, endosomes, Golgi apparatus, and cytoplasm [28].…”

Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity

“…Pgrmc1 KO mice presented a predisposition to steatohepatitis, non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma, and increased ER stress in the liver [ 178 , 243 ]. The loss of PGRMC1 seems to reduce the protection of hepatic cells against liver damage by the upregulation of alcohol-degrading enzymes, increasing acetaldehyde production and ER stress [ 244 ]. Surprisingly, CYP2E1 expression was demonstrated to be downregulated in Pgrmc1 KO mice [ 244 ], which supports the results obtained by the earlier McGuire et al study and the role of PGRMC1 in CYP protein stabilization [ 162 ].…”

“…The loss of PGRMC1 seems to reduce the protection of hepatic cells against liver damage by the upregulation of alcohol-degrading enzymes, increasing acetaldehyde production and ER stress [ 244 ]. Surprisingly, CYP2E1 expression was demonstrated to be downregulated in Pgrmc1 KO mice [ 244 ], which supports the results obtained by the earlier McGuire et al study and the role of PGRMC1 in CYP protein stabilization [ 162 ]. PGRMC1 was also reported to act as a size-selective cargo receptor to drive ER-phagocytotic clearance of mutant prohormones [ 245 ] and recruit misfolded proteins for this clearance [ 246 ].…”