Introduction

Alcoholic steatohepatitis (ASH) is a severe form of alcoholic liver disease (ALD) characterized by the presence of steatosis and inflammation. Kinases p38 γ/δ have been found to be involved in liver steatosis and inflammation, and have a significant role in the development of non-alcoholic liver disease caused by high-fat diets.

Aims & Methods

The objective of this study was to investigate the role of p38 γ/δ kinases in a murine model of alcoholic steatohepatitis (ASH) and to analyze the reduction of steatosis and inflammation in p38 γ/δ knock-out (KO) mice treated with ethanol (ETOH).
Wild-type (WT) and p38 γ/δ KO male mice were fed a chronic and binge ethanol diet (NIAAA model) to induce liver damage. Histopathological analysis was performed after Oil Red staining. The molecular effects of ethanol in the liver were explored through qPCR and western blot.

Results

Ethanol-treated KO (ETOH KO) mice showed a smaller liver size, decreased liver steatosis after histopathological analysis, and lower expression of inflammatory cytokines compared to ethanol-treated WT mice. The NIAAA diet caused oxidative stress and mTOR pathway activation in the liver in both ETOH WT and ETOH KO. ETOH WT mice had p62 phosphorylated at Thr269 and Ser272, which was reduced in ETOH KO mice.

Conclusion

The knockout of p38 γ/δ alleviates ALD in mice by reducing inflammation and steatosis. Alcoholic diet increased oxidative stress and inhibited autophagic pathways and p38 γ/δ KO restored, at least in part, this inhibition. (Supported by Instituto de Salud Carlos III and the European Union FEDER funds, “Una manera de hacer Europa” (PI20/00743) and Junta de Castilla y León, Spain (GRS 2648/A/22)).

References

González‐Terán B, Matesanz N, Nikolic I et al. p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration. EMBO J. 2016 Mar 1;35(5):536‐52.

Introduction

Alcohol-associated liver disease (ALD) is the most prevalent type of chronic liver disease worldwide. In contrast to their well-known association with type 2 immunity and allergies, a profound characterization and functional studies describing the properties of high systemic IgE levels observed during ALD are lacking.

Aims & Methods

Here, we aimed to address the functional role of IgE in ALD. To study the influence of IgE on ALD, we applied chronic-binge ethanol feeding (NIAAA model) to IgE-deficient (Igh7^-/-) and FcεRIα-deficient mice (FcεRIα^-/-), and their respective wild-type littermate controls. To investigate underlying mechanisms causing IgE elevation, we conducted studies involving the depletion of CD4⁺ T cells. Moreover, we performed anti-IgE treatment during ethanol feeding to evaluate the therapeutic potential of targeting IgE in ALD. In addition, IgE plasma levels and associated laboratory parameters were correlated to liver disease severity in ALD patients.

Results

As in human ALD, alcohol intake in mice increased circulating IgE, partly directed against intestinal food antigens. Antibody-mediated CD4⁺ T cell depletion as well as IL4Rα-deficiency in ethanol-fed mice prevented IgE elevation. Moreover, Il4 and Il13 transcription was increased in the small intestines of mice and in human duodenal samples during ALD, suggesting that IgE production occurs in the GI tract, and depends on a Th2 cytokine shift in the gut. Consistently, we observed increased eGLT transcription in mesenteric lymph nodes and intestinal lamina propria cells in murine ALD. Importantly, IgE- and FcεRIα-deficient mice showed less severe ethanol-induced steatohepatitis compared to wildtype littermates after chronic-binge ethanol diet, which associated with lower hepatic histamine levels. Furthermore, blocking free systemic IgE effectively prevented liver injury and inflammation in murine ALD. In line, systemic IgE titers in ALD patients associated with increased liver disease severity and correlated to plasma histamine levels. We also established that elevated serum IgE is a specific hallmark of alcohol-related liver injury compared to patients with other liver diseases, and that IgE levels decline with alcohol abstinence.

Conclusion

Our findings identify the Th2-IgE-FcεRIα-histamine signaling pathway as a novel critical mediator in the gut-liver axis during ALD progression, suggesting IgE and histamine as a promising therapeutic target.

Introduction

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by liver steatosis and inflammation which abnormal immune responses involved in pathogenesis, and there is no approved therapeutic drug. Rhein, one of the main bioactive components of Rheum palmatum, has exerted anti-inflammatory properties. However, the mechanism by which Rhein exerts beneficial effects against NASH is far from elucidated. Here, our study aimed to investigate the therapeutic effects of Rhein on liver steatosis and inflammation and elucidate the related mechanisms of immunoregulation.

Aims & Methods

Male C57BL/6 mice were given high-fat diet for 10 weeks to induce NASH, followed by Rhein suspension administration at a dose of 100mg/kg and 200mg/kg for 4 weeks. The therapeutic effect of NASH was estimated by body weight, liver weight, LW/BW, food intake, the liver appearance and the histological analysis of liver section stained with hematoxylin and eosin. The proportion of lymphocyte cells in the mesenteric lymph nodes (MLNs) was detected by flow cytometry.

Results

Our findings demonstrated that high-fat diet treatment resulted in severe liver inflammation and severe steatosis, while Rhein appreciably reverse these phenomenon, as evidenced by the reduction of body weight, liver wet weight, LW/BW, and liver size in mice. Histological analysis of liver section revealed that administration of Rhein exhibited improvement of severe steatosis, elimination of inflammatory cells and resolution of balloon-like changes when compared to mice in the HFD group. Interestingly, there were no significant differences in food intake among groups of mice, suggesting that the protective effect of Rhein is not achieved by inhibiting appetite. Mechanistically, flow cytometry analysis showed that higher Th1 and Th17 polarized response were detected in the MLN compartments in HFD-induced mice, evidenced by the detection of increased numbers of Th1 cells (CD3+CD4+IFN-γ+) and Th17 cells (CD3+CD4+IL-17+), and Rhein intervention showed significant decrease numbers of Th1 and Th17 in MLNs. In contrast, Rhein treatment significantly increased the numbers of Treg cells (CD3+CD4+Foxp3+) with anti-inflammatory effects in the MLN of NASH mice.

Conclusion

Our results provide novel insights into the protective role of Rhein in modulating the liver steatosis and inflammation, with therapeutic potential for immunology-targeted strategy in the treatment of NASH.

References

[1] Cheng L, Chen Q, Pi R, Chen J. A research update on the therapeutic potential of rhein and its derivatives. Eur J Pharmacol. 2021,899:173908. doi:10.1016/j.ejphar.2021.173908.
[2] Gebru YA, Gupta H, Kim HS, et al. T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Int J Mol Sci. 2021,22(22):12190. doi:10.3390/ijms222212190

Disclosure

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Introduction

Sirtuin 1 (SIRT1) regulates mitochondrial function and biogenesis, carbohydrate and lipid metabolism, oxidative stress, inflammation, and apoptosis. All these factors play a role in the development and progression of non-alcoholic fatty liver disease (NAFLD).

Aims & Methods

The aim of the study was to investigate the role of SIRT1 in the development and progression of NAFLD under the influence of stress factors during wartime. The serum SIRT1 level was determined using an enzyme-linked immunosorbent assay (ELISA) with the "Human SIRT1 (Sirtuin 1) ELISA Kit." Visceral fat tissue (VFT) was measured using an OMRON BF-511 electronic device. Liver function tests, carbohydrate and lipid metabolism parameters, and C-reactive protein (CRP) levels were assessed using standard methods on an automatic biochemical analyzer "HumaStar 300SR." Statistical analysis was performed using the SPSS 17.0 statistical software package.

Results

A total of 88 NAFLD patients with metabolic disorders were examined, including 57 individuals (main group) who were exposed to war-related stress factors and 31 individuals (comparison group) examined in the pre-war period. It was found that SIRT1 levels were significantly higher in the main group, averaging 8.88 ± 0.23 ng/mL, compared to 4.75 ± 0.14 ng/mL in the comparison group (p < 0.05). Subgroup analysis showed a trend towards higher SIRT1 levels in normal-weight patients compared to those who were overweight or obese in the main group. A direct correlation was found between SIRT1 levels and VFT in both groups: r = 0.32 in the main group and r = 0.24 in the comparison group. Meanwhile, SIRT1 levels exhibited a weak negative correlation with abdominal obesity parameters (waist-to-hip ratio): r = -0.14 in the main group and r = -0.12 in the comparison group. A weak negative correlation was also observed between fasting glucose and insulin levels and SIRT1 (r = -0.17 and r = -0.24, respectively). However, an inverse correlation trend was demonstrated between SIRT1 and the HOMA index (r = -0.33). Correlation analysis results also indicated a weak negative relationship between SIRT1 levels and total cholesterol (r = -0.21) and a strong negative correlation between SIRT1 and triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) (r = -0.37). At the same time, a weak positive correlation was observed between SIRT1 and high-density lipoprotein cholesterol (HDL-C) (r = 0.11). When comparing CRP levels, hepatocyte cytolysis enzymes, and SIRT1, a weak inverse correlation was found with CRP and ALT levels (r = -0.17 and r = -0.22, respectively).

Conclusion

The results of our study provide evidence of the significant role of SIRT1 in regulating liver inflammation and the development and progression of NAFLD.

Disclosure

No conflict of interest