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Protein Arginine methyltransferase 1 (PRMT1) is the main enzyme of cellular arginine methylation. Previously we found that PRMT1 activity in the liver is altered after alcohol exposure resulting in epigenetic changes. To determine the impact of these PRMT1 changes on the liver’s response to alcohol, we induced a hepatocyte specific PRMT1 knockout using AAV mediated Cre delivery in mice fed either alcohol or control Lieber-DeCarli liquid diet. We found that in alcohol fed mice, PRMT1 prevents oxidative stress and promotes hepatocyte survival. PRMT1 knockout in alcohol fed mice resulted in a dramatic increase in hepatocyte death, inflammation and fibrosis. Additionally, we found that alcohol promotes PRMT1 dephosphorylation at S297. Phosphorylation at this site is necessary for PRMT1-dependent protein arginine methylation. PRMT1 S297A, a dephosphorylation mimic of PRMT1 had reduced ability to promote gene expression of pro-inflammatory cytokines, pro-apoptotic genes BIM and TRAIL and expression of a suppressor of hepatocyte proliferation, Hnf4α. On the other hand, several functions of PRMT1 were phosphorylation-independent, including expression of oxidative stress response genes, Sod1, Sod2 and others. In vitro , both wild type and S297A PRMT1 protected hepatocytes from oxidative stress induced apoptosis, however S297D phosphorylation mimic PRMT1 promoted cell death. Taken together these data suggest that PRMT1 is an essential factor of liver adaptation to alcohol; alcohol-induced dephosphorylation shifts PRMT1 toward a less pro-inflammatory, more pro-proliferative and pro-survival form.

Alcohol‐associated liver disease (ALD) is a major cause of alcohol‐related mortality. Sex differences in sensitivity to ALD are well described, but these are often disregarded in studies of ALD development. We aimed to define sex‐specific pathways in liver exposed to alcohol. Mice were fed the Lieber‐DeCarli alcohol liquid diet or a combination of a high‐fat diet with alcohol in water. Single‐cell RNA sequencing (scRNA‐Seq) was performed on liver cells from male and female mice. Mice were treated with adeno‐associated virus (AAV)‐short hairpin (sh)Control or AAV‐sh lysine demethylase 5b (shKdm5b) and/or AAV‐shKdm5c vectors. Changes after Kdm5b/5c knockdown were assessed by RNA‐Seq and histone H3 lysine K4 (H3K4)me3 chromatin immunoprecipitation‐Seq analysis. Using scRNA‐Seq analysis, we found several sex‐specific pathways induced by alcohol, including pathways related to lipid metabolism and hepatocyte differentiation. Bioinformatic analysis suggested that two epigenetic regulators, H3K4‐specific lysine demethylases KDM5B and KDM5C, contribute to sex differences in alcohol effects. We found that in alcohol‐fed male mice, KDM5B and KDM5C are involved in hepatocyte nuclear factor 4 alpha (Hnf4a) down‐regulation, hepatocyte dedifferentiation, and an increase in fatty acid synthesis. This effect is mediated by alcohol‐induced KDM5B and KDM5C recruitment to Hnf4a and other gene promoters in male but not in female mice. Kdm5b and Kdm5c knockdown or KDM5‐inhibitor treatment prevented alcohol‐induced lipid accumulation and restored levels of Hnf4a and other hepatocyte differentiation genes in male mice. In addition, Kdm5b knockdown prevented hepatocellular carcinoma development in male mice by up‐regulating Hnf4a and decreasing tumor cell proliferation. Conclusion: Alcohol specifically activates KDM5 demethylases in male mice to promote alcohol‐induced hepatocyte dedifferentiation and tumor development.

Alcohol is a well‐established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which alcohol promotes liver cancer are not well understood. Studies suggest that ethanol may enhance tumor progression by increasing hepatocyte proliferation and through alcohol‐induced liver inflammation. Protein arginine methyltransferase 1 (PRMT1) is the main enzyme responsible for cellular arginine methylation. Asymmetric dimethyl arginine, produced by PRMT1, is a potent inhibitor of nitric oxide synthases. PRMT1 is implicated in the development of several types of tumors and cardiovascular disease. Our previous work has shown that PRMT1 in the liver regulates hepatocyte proliferation and oxidative stress and protects from alcohol‐induced liver injury. However, its role in HCC development remains controversial. In this study, we found that hepatocyte‐specific PRMT1‐knockout mice develop an increased number of tumors in an N‐nitrosodiethylamine (DEN) alcohol model of liver tumorigenesis in mice. This effect was specific to the alcohol‐related component because wild‐type and knockout mice developed similar tumor numbers in the DEN model without the addition of alcohol. We found that in the presence of alcohol, the increase in tumor number was associated with increased proliferation in liver and tumor, increased WNT/β‐catenin signaling, and increased inflammation. We hypothesized that increased inflammation was due to increased oxidative and nitrosative stress in knockout mice. By blocking excess nitric oxide production using an inducible nitric oxide synthase inhibitor, we reduced hepatocyte death and inflammation in the liver and prevented the increase in WNT/β‐catenin signaling, proliferation, and tumor number in livers of knockout mice. Conclusion: PRMT1 is an important protection factor from alcohol‐induced liver injury, inflammation, and HCC development. PRMT1 has multiple targets that can either promote or suppress tumor growth depending on the environmental conditions. In the presence of alcohol, PRMT1 suppresses tumor development in mice via regulation of iNOS activity‐dependent liver inflammation and beta‐catenin signaling. By inhibiting iNOS in PRMT1 knockout mice we were able to reduce hepatocyte death, inflammation and proliferation as well as tumor development in alcohol fed mice.

Alcohol‐associated liver disease is a major cause of alcohol‐related mortality. However, the mechanisms underlying disease progression are not fully understood. Recently we found that liver molecular pathways are altered by alcohol consumption differently in males and females. We were able to associate these sex‐specific pathways with two upstream regulators: H3K4‐specific demethylase enzymes KDM5B and KDM5C. Mice were fed the Lieber‐DeCarli alcohol liquid diet for 3 weeks or a combination of a high‐fat diet with alcohol in water for 16 weeks (western diet alcohol model [WDA] model). To assess the role of histone demethylases, mice were treated with AAV‐shControl, AAV‐shKdm5b, and/or AAV‐shKdm5c and/or AAV‐shAhR vectors. Gene expression and epigenetic changes after Kdm5b/5c knockdown were assessed by RNA‐sequencing and H3K4me3 chromatin immunoprecipitation analysis. We found that less than 5% of genes affected by Kdm5b/Kdm5c knockdown were common between males and females. In females, Kdm5b/Kdm5c knockdown prevented fibrosis development in mice fed the WDA alcohol diet for 16 weeks and decreased fibrosis‐associated gene expression in mice fed the Lieber‐DeCarli alcohol liquid diet. In contrast, fibrosis was not affected by Kdm5b/Kdm5c knockdown in males. We found that KDM5B and KDM5C promote fibrosis in females through down‐regulation of the aryl hydrocarbon receptor (AhR) pathway components in hepatic stellate cells. Kdm5b/Kdm5c knockdown resulted in an up‐regulation of Ahr, Arnt, and Aip in female but not in male mice, thus preventing fibrosis development. Ahr knockdown in combination with Kdm5b/Kdm5c knockdown restored profibrotic gene expression. Conclusion: KDM5 demethylases contribute to differences between males and females in the alcohol response in the liver. The KDM5/AhR axis is a female‐specific mechanism of fibrosis development in alcohol‐fed mice. In this study we report that in female mice, alcohol induces KDM5B and KDM5C in hepatic stellate cells to promote AhR downregulation and fibrosis development; liver knockdown of Kdm5b and Kdm5c can prevent AhR downregulation and fibrosis development in females but not in males. Relationship between KDM5 demethylases and fibrosis is female specific in humans as well. Potentially our study is the first step to future sex‐specific therapy for Alcohol‐associated Liver Disease.

Protein arginine methyl transferase 1 (PRMT1) is the main enzyme for cellular arginine methylation. It regulates many aspects of liver biology including inflammation, lipid metabolism, and proliferation. Previously we identified that PRMT1 is necessary for protection from alcohol‐induced liver injury. However, many PRMT1 targets in the liver after alcohol exposure are not yet identified. We studied the changes in the PRMT1‐dependent arginine methylated proteome after alcohol feeding in mouse liver using mass spectrometry. We found that arginine methylation of the RNA‐binding protein (heterogeneous nuclear ribonucleoprotein [hnRNP]) H1 is mediated by PRMT1 and is altered in alcohol‐fed mice. PRMT1‐dependent methylation suppressed hnRNP H1 binding to several messenger RNAs of complement pathway including complement component C3. We found that PRMT1‐dependent hnRNP H methylation suppressed complement component expression in vitro, and phosphorylation is required for this function of PRMT1. In agreement with that finding, hepatocyte‐specific PRMT1 knockout mice had an increase in complement component expression in the liver. Excessive complement expression in alcohol‐fed PRMT1 knockout mice resulted in further complement activation and an increase in serum C3a and C5a levels, which correlated with inflammation in multiple organs including lung and adipose tissue. Using specific inhibitors to block C3aR and C5aR receptors, we were able to prevent lung and adipose tissue inflammation without affecting inflammation in the liver or liver injury. Conclusion: Taken together, these data suggest that PRMT1‐dependent suppression of complement production in the liver is necessary for prevention of systemic inflammation in alcohol‐fed mice. C3a and C5a play a role in this liver–lung and liver–adipose interaction in alcohol‐fed mice deficient in liver arginine methylation.

Now, much is known regarding the impact of chronic and heavy alcohol consumption on the disruption of physiological liver functions and the induction of structural distortions in the hepatic tissues in alcohol-associated liver disease (ALD). This review deliberates the effects of alcohol on the activity and properties of liver non-parenchymal cells (NPCs), which are either residential or infiltrated into the liver from the general circulation. NPCs play a pivotal role in the regulation of organ inflammation and fibrosis, both in the context of hepatotropic infections and in non-infectious settings. Here, we overview how NPC functions in ALD are regulated by second hits, such as gender and the exposure to bacterial or viral infections. As an example of the virus-mediated trigger of liver injury, we focused on HIV infections potentiated by alcohol exposure, since this combination was only limitedly studied in relation to the role of hepatic stellate cells (HSCs) in the development of liver fibrosis. The review specifically focusses on liver macrophages, HSC, and T-lymphocytes and their regulation of ALD pathogenesis and outcomes. It also illustrates the activation of NPCs by the engulfment of apoptotic bodies, a frequent event observed when hepatocytes are exposed to ethanol metabolites and infections. As an example of such a double-hit-induced apoptotic hepatocyte death, we deliberate on the hepatotoxic accumulation of HIV proteins, which in combination with ethanol metabolites, causes intensive hepatic cell death and pro-fibrotic activation of HSCs engulfing these HIV- and malondialdehyde-expressing apoptotic hepatocytes.

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.

Alcohol is a well-established risk factor for hepatocellular carcinoma, but the mechanisms are not well understood. Several studies suggested that alcohol promotes tumor growth by altering immune cell phenotypes in the liver. Arginine methylation is a common posttranslational modification generated mostly by a single protein, PRMT1. In myeloid cells PRMT1 is a key regulator of immune response. Myeloid-specific PRMT1 knockout mice are hyperresponsive to LPS and deficient in PPARγ-dependent macrophage M2 polarization. We aimed to define the role of myeloid PRMT1 in alcohol-associated liver tumor progression using a mouse model of DEN injection followed by Lieber-DeCarli alcohol liquid diet feeding. We found that PRMT1 knockout mice showed significantly lower expression of IL-10 and IL-6 cytokines in the liver and downstream STAT3 activation, which correlated with reduced number of surface tumors, reduced proliferation, and reduced number of M2 macrophages in the liver as well as within proliferating nodules. We found that blocking IL-6 signaling in alcohol-fed mice reduced the number of tumors and liver proliferation in wild-type mice but not in knockout mice suggesting that reduced IL-6 in PRMT1 knockout mice contributes to the protection from alcohol. Additionally, PRMT1 knockout did not show any protection in tumor formation in the absence of alcohol. Finally, we confirmed that this mechanism is relevant in humans. We found that PRMT1 expression in tumor-associated macrophages correlated with STAT3 activation in human HCC specimens. Taken together, these data suggest that the PRMT1-IL-6-STAT3 axis is an important mechanism of alcohol-associated tumor progression.

Protein arginine methyl transferase 1 (PRMT1) is the main enzyme for cellular arginine methylation. It regulates many aspects of liver biology including inflammation, lipid metabolism, and proliferation. Previously we identified that PRMT1 is necessary for protection from alcohol‐induced liver injury. However, many PRMT1 targets in the liver after alcohol exposure are not yet identified. We studied the changes in the PRMT1‐dependent arginine methylated proteome after alcohol feeding in mouse liver using mass spectrometry. We found that arginine methylation of the RNA‐binding protein (heterogeneous nuclear ribonucleoprotein [hnRNP]) H1 is mediated by PRMT1 and is altered in alcohol‐fed mice. PRMT1‐dependent methylation suppressed hnRNP H1 binding to several messenger RNAs of complement pathway including complement component C3. We found that PRMT1‐dependent hnRNP H methylation suppressed complement component expression in vitro, and phosphorylation is required for this function of PRMT1. In agreement with that finding, hepatocyte‐specific PRMT1 knockout mice had an increase in complement component expression in the liver. Excessive complement expression in alcohol‐fed PRMT1 knockout mice resulted in further complement activation and an increase in serum C3a and C5a levels, which correlated with inflammation in multiple organs including lung and adipose tissue. Using specific inhibitors to block C3aR and C5aR receptors, we were able to prevent lung and adipose tissue inflammation without affecting inflammation in the liver or liver injury. Conclusion: Taken together, these data suggest that PRMT1‐dependent suppression of complement production in the liver is necessary for prevention of systemic inflammation in alcohol‐fed mice. C3a and C5a play a role in this liver–lung and liver–adipose interaction in alcohol‐fed mice deficient in liver arginine methylation.

Protein arginine methyl transferase 1 (PRMT1) is the main enzyme for cellular arginine methylation. It regulates many aspects of liver biology including inflammation, lipid metabolism, and proliferation. Previously we identified that PRMT1 is necessary for protection from alcohol-induced liver injury. However, many PRMT1 targets in the liver after alcohol exposure are not yet identified. We studied the changes in the PRMT1-dependent arginine methylated proteome after alcohol feeding in mouse liver using mass spectrometry. We found that arginine methylation of the RNA-binding protein (heterogeneous nuclear ribonucleoprotein [hnRNP]) H1 is mediated by PRMT1 and is altered in alcohol-fed mice. PRMT1-dependent methylation suppressed hnRNP H1 binding to several messenger RNAs of complement pathway including complement component C3. We found that PRMT1-dependent hnRNP H methylation suppressed complement component expression , and phosphorylation is required for this function of PRMT1. In agreement with that finding, hepatocyte-specific PRMT1 knockout mice had an increase in complement component expression in the liver. Excessive complement expression in alcohol-fed PRMT1 knockout mice resulted in further complement activation and an increase in serum C3a and C5a levels, which correlated with inflammation in multiple organs including lung and adipose tissue. Using specific inhibitors to block C3aR and C5aR receptors, we were able to prevent lung and adipose tissue inflammation without affecting inflammation in the liver or liver injury. Taken together, these data suggest that PRMT1-dependent suppression of complement production in the liver is necessary for prevention of systemic inflammation in alcohol-fed mice. C3a and C5a play a role in this liver-lung and liver-adipose interaction in alcohol-fed mice deficient in liver arginine methylation.