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Indian Journal of Pharmacology logoLink to Indian Journal of Pharmacology
. 2026 May 1;58(3):215–223. doi: 10.4103/ijp.ijp_26_24

Discovery of the protective effect of glutamine on acute alcoholic liver injury

Huan Yang 1,2, Wei Guo 1,2, San-Qiang Li 1,2,✉, Bing-Bing Zhang 1,2, Dan Wang 3, Wei-Gang Cheng 3, Shuning Chen 4
PMCID: PMC13258285  PMID: 42060805

Abstract

OBJECTIVE:

Our research aims to evaluate the important role of glutamine (Gln) in alcohol (ethanol)-induced liver damage.

MATERIALS AND METHODS:

In our study, the mice were simultaneously divided into normal group, alcohol group, and Gln+alcohol group. After different treatments, we detected alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver index. Then, some histopathological examination was used to observe the damage of liver tissue, glycogen, and liver cell apoptosis in mice. In addition, the expression of apoptosis-related proteins Bcl-2, Bax, Caspase3, heat stress protein 70 (HSP70), cytochrome cytochrome P450-2E1, NFκB pathway-related proteins IkB-a, NFκB-p65, and tumor necrosis factor-α were detected in different groups by western blotting. The experiment in vitro, we used normal hepatocytes L02, after treatment with alcohol and Gln for 24 h, carried out CCK-8 cell proliferation detection and western blotting to detect the expression of related proteins.

RESULTS:

Our results showed that, in serological testing, Gln can significantly reduce the levels of ALT, AST, and liver index in Gln+alcohol group; and in the histopathological examination, Gln can increase the glycogen content and decrease the apoptosis rate in Gln+alcohol group. In addition, the differential expression of IκBα, NFκB-p65, and other factors in Western blotting shows that the NFκB signaling pathway plays important role in acute alcoholic liver injury.

CONCLUSIONS:

Our results showed that Gln played an important protective role in alcohol-induced liver injury in mice by regulating glycogen stores, apoptosis, anti-oxidative stress and inhibiting NF-κB signaling pathways in liver cells.

Keywords: Acute liver injury, alcohol, glutamine, mechanism, protective effect

Introduction

Alcohol-induced liver diseases have posed a significant threat to human health, and several methods for preventing and treating alcoholic liver injury have been developed worldwide, including alcohol withdrawal therapy, drug therapy, surgical therapy, dietary therapy, and others.[1]

Let’s imagine if given corresponding drug therapy during a certain or short-term stage of acute alcoholic liver injury caused by excessive alcohol consumption can eliminate alcoholic liver disease in the embryonic stage, so as to effectively reduce the incidence rate of alcoholic liver disease. Therefore, we reviewed previous research results and found that glutamine (Gln) is a very interesting substance, it participates in the synthesis of four major macromolecules in the cytoplasmic sol: Proteins, nucleotides, lipids, and fatty acids.[2] It is the most abundant nonessential amino acid in the cycle.[3] It can maintain the integrity of the intestinal mucosa, maintain the function of the immune system, and reduce the incidence of infection.[4] Besides, there is evidence to suggest that Gln metabolism is closely related to the regulation of vascular sprouting, vasodilation, and redox homeostasis, and Gln is the amino acid consumed by endothelial cells the most.[3] Huang et al.[5] found that endothelial cells lacking Gln are more sensitive to reactive oxygen species (ROS) induced cell death, partly due to reduced production of glutathione. These findings highlight the importance of Gln metabolism in maintaining endothelial cell redox homeostasis.[6]

In summary, multiple studies have shown that supplementing Gln has beneficial effects.[7,8,9,10] In our experiment, Gln demonstrated a good protective effect on acute alcoholic liver injury, which provides a preliminary basis for effectively enriching our intervention therapy in the stage of acute alcoholic liver injury.

Materials and Methods

Experimental animal

The 30 healthy male 8-week-old C57BL/6 mice (weight 19–23 g) were provided by Liaoning Changsheng Biotechnology Co., Ltd., mouse certificate number: Scxk (Liao) 2015-0001. Adaptive feeding for 1 week. The living environment of the mice is kept constant, that is, the temperature is 22°C ± 2°C, the humidity is 54% ±10%, and the environment is sanitary and clean with normal ventilation, alternate day and night, and the mice are free to drink and eat.

Experimental reagents and methods

In vivo experiment: 30 healthy and clean C57BL/6 male mice were randomly divided into normal group, alcohol group, and Gln+alcohol group, with 10 mice in each group. The normal group was fed normally for 7 days. The alcohol group was given 56% liquor (12 mL/kg) per day for 7 consecutive days; the Gln+alcohol group was given L-Gln dissolved in distilled water(800 mg/kg/d), the dose of 800 mg/kg/d has been proven effective in previous trials[11] for 7 consecutive days and then given 56% liquor (12 mL/kg) gavage; after 24 h, the mice were dissected and their livers were weighed; liver index = mouse liver weight/body weight × 100%, and then various indicators were tested and observed.

Detection of aspartate aminotransferase and alanine aminotransferase activity

After 24 h of modeling, blood samples were collected from the mouse eyeballs and the serum was separated. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was determined by automatic biochemical analyzer according to the kit instructions.

Hematoxylin and eosin staining to detect liver damage in each group of mice

The paraffin sections of liver tissue were baked and then put into gradient xylene and ethanol liquids of different concentrations for hydration. Start dying with hematoxylin. Then differentiate with hydrochloric acid, add ammonia solution to return to blue, stain with eosin, and finally perform gradient dehydration, and seal the slides with neutral resin. Hematoxylin and eosin staining liver tissue damage scoring standard: Accumulation of neutral fat: <5% is 0 points, 5%–33% is 1 point, 33%–67% is 2 points, and >67% is 3 points. Hepatitis: 0 points for no inflammatory lesions, 1 point for <2 inflammatory lesions, 2 points for 2–4 inflammatory lesions, 3 points for more than 4 inflammatory lesions. Cell swelling: 0 points for no inflammatory lesions, 1 point for a small amount of visibility, and 2 points for a large amount of visibility.

Observation of glycogen in mouse liver after periodic acid Schiff staining

First, roast the slices, dewax, and hydrate (the method is the same as described above), then, in a dark place, oxidize them with periodic acid reagent, stain with Schiff reagent, stain the nucleus with hematoxylin staining solution, and then perform dehydration and mounting; Finally, the glycogen status of the liver tissue was observed and photographed under a 200-fold ordinary optical microscope, and the results were analyzed with Image J software.

Hoechst 33258 kit to detect apoptosis in mouse liver cells

First, roast the slices, dewax, and hydrate (the method is the same as described above), then, wash with Phosphate buffer saline (PBS) twice, suck up the liquid with a pipette, add 0.3 ml Hoechst 33258 dye solution, and dye for 5 min in the dyeing box in the dark. Rinse again with PBS for two times, after sucking up the liquid, mount the slide for storage; observe and take pictures under a fluorescent microscope, and use Image J software to count the number of apoptotic cells.

Western blotting was used to detect the expression of apoptosis protein Bcl-2, Bax, Caspase3, heat stress protein 70 (HSP70), cytochrome cytochrome P450-2E1, NFκB pathway related proteins IκBα, NB-p65, and tumor necrosis factor-α

Grind the liver tissues of each group separately, extract the tissue protein, use the protein concentration kit to detect the protein concentration, and add the electrophoresis loading buffer (50 mM Tris, pH 6.8, 10% glycerol, 5% beta-mercaptoethanol, 2% sodium dodecyl sulfate, 0.1% bromphenol blue).[12] Boil them in boiling water for 5 min and load them in an amount of 50 μg; then prepare the gel and transfer the protein from the gel to the nitrocellulose membrane. The membrane was probed with monoclonal antibodies against mouse Bcl-2, Bax, Caspase3, The HSP70 is heat shock protein 70 in our study, cytochrome P450-2E1 (CYP2E1), IκBα, NFκB-p65, and tumor necrosis factor-α (TNF-α). Add DAB for color development or use Tanon-4600 exposure machine for exposure, and then observe the expression of target protein bands. Finally, take a picture of the target frequency band and use Image J software to analyze it. Each experiment was repeated three times.

Cell culture and ethanol treatment

Normal liver cells L02 were purchased from the Institute of Biomedicine, Fudan University, Shanghai. Put them in a 37°C cell incubator for culture. The cell culture medium is DMEM containing 10% fetal bovine serum; L02 cells were inoculated into a 96-well plate and cultured normally, and then randomly divided into three groups and then labeled: Normal group: Cells were cultured routinely, after the cells were overgrown, cultured with Gln-free medium for 24 h; alcohol group: Normal culture, after the cells grow up, add culture medium without Gln and 30 μl/ml alcohol concentration for 24 h; Gln+alcohol group: Normal culture, after the cells grow up, add 0.01 mol/L Gln[13] (which was proven effective in previous experiments) and 30 μl/ml alcohol medium for 24 h; experimental items: (1) CCK-8 cell activity detection; (2) Western blotting method to detect the expression of related factors: Caspase-3, HSP70, P4502E1 (CYP2E1), IκB-α, NFκB-p65.

CCK-8 cell viability detection

After trypsin digestion of the cells, they are inoculated into 96-well plates and labeled as: Normal group; alcohol group; Gln+alcohol group; after 24 h of culture, add 10 μl of CCK-8 reagent. Then place it in the cell culture incubator for 1 h and then use a microplate reader to detect the absorbance at 450 nm and calculate the survival rate. Each group set 6 reactions empty and repeat the experiment three times independently.

Western blot protein detection

Cell protein was extracted, and the expression of Bcl-2, Bax, Caspase3, HSP70, CYP2E1, IκBα, NFκB-p65 and TNF-α were detected in each group by Western blotting (the same method as above).

Statistical analysis of experimental data

All quantitative data were statistically calculated with SPSS 25.0 statistical software (Spss inc., Chicago, Illinois, USA). Except for the Kruskal–Wallis test statistical analysis of the median of liver necrosis score, all other experimental data were subjected to the one-way analysis of variance to compare the differences between the samples in each group, P < 0.05, P < 0.01, and P < 0.001 indicate that the difference is statistically significant, but the test level is different.

Results

Detection of alanine aminotransferase, aspartate aminotransferase enzyme activity, and liver index

AST, ALT and liver index are the common indicators of liver damage. After alcohol gavage for 24 h, compared with normal group, the ALT and AST test values of alcohol group were significantly increased (P < 0.01), and the liver index was significantly increased (P < 0.01); Gln+alcohol group was significantly lower than the test values of ALT and AST in alcohol group (P < 0.01), the liver index was significantly reduced (P < 0.01); indicating that Gln can reduce alcohol-induced acute liver injury in mice [Figure 1].

Figure 1.

Figure 1

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(a) Liver index, (b) Serum aspartate aminotransferase, (c) Serum alanine aminotransferase. The normal group was fed normally for 7 days. The alcohol group was given 56% liquor (24 mL/kg) per day for 7 consecutive days, the glutamine (Gln)+Alcohol group was given L-Gln dissolved in distilled water for 7 consecutive days and then given 56% liquor (12 mL/kg) gavage. All data are presented as the mean ± standard deviation. ***P < 0.001: There was a significant difference between these two different groups. Experiments were repeated in triplicate. ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, Gln: Glutamine

Hematoxylin and eosin staining results and hepatocyte necrosis score

The liver tissue cells of the mice in normal group are neatly arranged, the structure is normal, the cytoplasm is clear, and there are almost no obvious pathological changes; the liver cells of the mice in alcohol group are arranged disorderly with loose cytoplasm, uneven size and obvious edema-like necrosis. Although the cell arrangement of Gln+alcohol group is still disordered, swelling is basically not seen, and the pathological degree of Gln+alcohol group has been greatly relieved compared with alcohol group, indicating that Gln reduces the necrosis score of liver tissue and reduces liver damage [Figure 2].

Figure 2.

Figure 2

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Histological examination of liver injury in mice by hematoxylin and eosin staining. (a) Liver damage of the normal group, (b) Liver damage of the alcohol group, (c) Liver damage of the Gln+Alcohol group, (d) Area of necrosis. Measurements of liver sections of at least 10 mm2 per mouse were performed using ImagePro plus 6.0 software. ***P < 0.001: There was a significant difference between these two different groups, *P < 0.05: There was a significant difference between these two different groups. Experiments were repeated in triplicate (scale bar, 50 µm). Gln: Glutamine

Periodic acid Schiff staining results

Periodic acid Schiff’s (PAS) staining can stain starch and glycogen in mouse liver cells into purple-red. After intragastric administration with alcohol for 24 h, the PAS glycogen staining in the liver tissues of mice in normal group was observed under microscope, indicating that there was more glycogen distribution; the liver cells of mice in alcohol group were damaged severely, and glycogen was needed to repair the damage and consume sugar. There are more glycogen, so glycogen was significantly reduced compared with normal group (P < 0.001); because liver tissue damage in Gln+alcohol group was reduced, glycogen content was significantly increased compared with alcohol group (P < 0.05), but it was still significantly lower than normal group (P < 0.01) indicating that Gln can reduce liver damage and reduce glycogen consumption [Figure 3].

Figure 3.

Figure 3

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The results of periodic acidSchiff (PAS) staining assay of staining at 24 h after alcohol gavage. (a) Liver PAS staining of the normal group, (b) Liver PAS staining of the alcohol group, (c) Liver PAS staining of the Gln+alcohol group, magnification value is (×200) in our study, (d) Average grayscale of glycogen in different groups. Two–color segmentation and optical density analysis using Motic Images Advanced 3.2 software. At least 12 mm2 of liver tissue sections were tested for each mouse. *P < 0.05: There was a significant difference between these two different groups, **P < 0.01: There was a significant difference between these two different groups, ***P < 0.001: There was a significant difference between these two different groups. Experiments were repeated in triplicate (scale bar, 50 μm). PAS: Periodic acidSchiff, Gln: Glutamine

Hoechst 33258 staining results of liver tissue

After the mice were given alcohol for 24 h, the proportion of apoptotic hepatocytes in the liver tissue of the three groups was observed by a fluorescence microscope; the alcohol group was significantly higher than that of the normal group (P < 0.001); the Gln+alcohol group was significantly reduced compared with the alcohol group (P < 0.001), indicating that Gln can reduce the degree of apoptosis of hepatocytes [Figure 4].

Figure 4.

Figure 4

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Results of Hochest 33258 staining assay of liver sections prepared from the mice at 24 h after alcohol gavage. (a) Hepatocyte apoptosis in the normalgroup, (b) Hepatocyte apoptosis in the alcohol group, (c) Hepatocyte apoptosis in the Gln+alcohol group, (d) Apoptosis rate. Measurements of liver sections of at least 10 mm2 per mouse were performed using ImagePro Plus 6.0 software. **P < 0.01: There was a significant difference between these two different groups, ***P < 0.001: There was a significant difference between these two different groups. Experiments were repeated in triplicate (scale bar, 50 μm). Gln: Glutamine

Western blot method to detect cell protein expression results

After the mice were given alcohol for 24 h, the expressions of Bax, Caspase-3, CYP2E1, NFκB-p65, and TNF-α in the Gln+alcohol group were significantly lower than those in the alcohol group (P < 0.01 or P < 0.05), and the expression content of alcohol group was significantly higher than that of normal group (P < 0.001). Compared with alcohol group, the protein expression of Bcl-2 and IκBα in mouse hepatocytes of Gln+alcohol group increased significantly (P < 0.05), while alcohol group was significantly reduced compared with normal group (P < 0.001). Compared with alcohol group, the protein expression of HSP70 in mouse hepatocytes of Gln+alcohol group was significantly increased (P < 0.05), while alcohol group was significantly increased compared with normal group [Figure 5].

Figure 5.

Figure 5

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Expression of P65, Bax, HSP70, Caspase3, Ikβ-a, cytochrome P450-2E1 (CYP2E1), Bcl-2 and tumor necrosis factor-α (TNF-α) in the liver of mice at 24 h After alcohol gavage. (a) Expression of P65, Bax, HSP70, Caspase3, Ikβ-a, CYP2E1, Bcl-2, and TNF-α protein was detected by western blot analysis. The protein bands were quantified for (b) P65, (c) Bax, (d) HSP70, (e) Caspase3, (f) Ikβ-a, (g) CYP2E1, (h) Bcl-2 and (i) TNF-α with the GelPro Analyzer 4.0 software (Media Cybernetics Inc.), and the intensities of the bands were normalized against Betaactin. Experiments were performed in triplicate, and all experimental data are expressed as the mean ± standard deviation. *P < 0.05: There was a significant difference between these two different groups, **P < 0.01: There was a significant difference between these two different groups, ***P < 0.001: there was a significant difference between these two different groups. CYP2E1: Cytochrome P450-2E1, TNF-α: Tumor necrosis factor-α

L02 cell survival rate detection

The results showed that the survival rates of alcohol group were significantly reduced compared with normal group after 24 h of cell injury caused by alcohol (P < 0.001). However, compared with alcohol group, the cell survival rate was significantly increased (P < 0.05) in Gln+alcohol group [Figure 6].

Figure 6.

Figure 6

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Cell survival rate. *P < 0.05: There was a significant difference between these two different groups, **P < 0.01: There was a significant difference between these two different groups, ***P < 0.001: There was a significant difference between these two different groups. Gln: Glutamine

Western blot method to detect cell protein expression results

Compared with alcohol group, the protein expression of HSP70 in Gln+alcohol group increased significantly (P < 0.05), and alcohol group increased significantly compared with normal group (P < 0.05). Compared with alcohol group, the protein expression of IκBα in Gln+alcohol group was significantly increased (P < 0.05) and alcohol group was significantly reduced compared with normal group (P < 0.001). The protein expression of Caspase-3, CYP2E1, and NFκB-p65 in the Gln+alcohol group was significantly lower than that in the alcohol group (P < 0.01 or P < 0.05), while the alcohol group was significantly higher than the normal group (P < 0.001) [Figure 7].

Figure 7.

Figure 7

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Expression of HSP70, Caspase3, cytochrome P450-2E1 (CYP2E1), Ikβ-a and P65 in the liver cell of mice after 24 h of culture. (a) Expression of HSP70, Caspase3, CYP2E1, Ikβ-a, and P65 protein was detected by the western blot analysis. The protein bands were quantified for (b) HSP70, (c) Caspase3, (d) CYP2E1, (e) Ikβ-a and (f) P65 with the GelPro Analyzer 4.0 software (Media Cybernetics Inc.), and the intensities of the bands were normalized against Betaactin. Experiments were performed in triplicate, and all experimental data are expressed as the mean ± standard deviation. *P < 0.05: There was a significant difference between these two different groups, **P < 0.01: There was a significant difference between these two different groups, ***P < 0.001: There was a significant difference between these two different groups. CYP2E1: Cytochrome P450-2E1

Discussion

This study found that Gln plays an important protective role in alcohol (ethanol)-induced acute liver injury in mice for the first time.

The results of AST, ALT, liver index, and histopathological staining showed that the intervention of Gln reduced the levels of serum AST and ALT, at the same time, reduced the consumption of glycogen, reduced the rate of apoptosis, and thus reduced the necrosis of liver tissue.

Heat shock protein 70 (HSP70) plays an important role in protecting cells from adverse stresses such as ischemia, inflammation, and heat shock.[14] In addition, heat shock protein 70 can also induce cell protection by directly preventing the activation of NF-kB.[15] Compared with alcohol group, the protein expression of HSP70 in Gln+alcohol group increased significantly (P < 0.05), which has a protective effect on liver cells. Interestingly, it was found that the expression levels of Bax, Caspase-3, CYP2E1, NFκB-p65, and TNF-α were significantly reduced in Gln+alcohol group compared with alcohol group (P < 0.05, P < 0.01 or P < 0.001), the protein expression of Bcl-2 and IκBα increased significantly (P < 0.05).

Bcl-2 in cells has an anti-apoptotic effect, and Bax has a pro-apoptotic effect;[16] By preventing the release of cytochrome C or by binding to apoptotic protease activating factor-1, the Bcl-2 protein in the mitochondrial wall prevents the formation and appearance of apoptotic bodies;[17] Bax is a key protein in the Bcl-2 family that induces apoptosis.[18] In addition, Caspase-3 is also involved in apoptosis, and it is the most critical executor of apoptosis downstream of the caspase cascade. Our research found that the application of Gln promotes the decrease of Bax and Caspase-3 and the increase of Bcl-2; that is to say, Gln can weaken the pro-apoptotic effect of damaged liver cells and enhance the anti-apoptotic effect, thereby reducing the liver damage.

CYP2E1 enzyme is a member of the cytochrome P450 enzyme system and a core system member of drug metabolism distributed in the liver. Alcohol intake increases the production of reactive oxygen species ROS in microsomal CYP2E1.[19,20,21,22,23,24] The production of such ROS can induce apoptosis and inflammation,[20,21] thereby aggravating alcoholic liver injury; our research has also confirmed this.

According to our results, severe liver damage in alcohol group mice resulted in the dissociation of NF-κB-p65 into the nucleus, so the expression of NF-κB-p65 in the nucleus was significantly increased (P < 0.001), while IκBα decreased (P < 0.001). This led to the activation of the NF-κB pathway, thereby generating inflammatory factors and causing an increase in TNF-α (P < 0.001). TNF-α is a pleiotropic cytokine that can induce cell proliferation or cell death. Inhibition of NF-κB activation will increase the sensitivity to TNFα-induced death;[25] the corresponding TNF-α is also significantly reduced (P < 0.05), which is similar to the effect after the addition of Gln, indicating Gln can inhibit the NF-κB pathway by regulating the expression of p65 and IκBα, leading to the reduction of TNF-α and reducing the cascade of inflammation.

Our study on L02 cells showed that Gln can increase the survival rate of injured cells and reduce alcoholic liver injury. The expression of various factors in the results of cell protein expression detected by Western blotting also verified our conclusions.

Conclusions

Gln can effectively alleviate acute alcoholic liver injury in mice, and its mechanism is related to increasing glycogen reserve, anti-apoptosis of hepatocytes, anti-oxidative stress and inhibiting NFκB signaling pathway.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

This work was supported by National Natural Science Foundation of China (82170606), Basic Research Project of Key Scientific Research Projects of Universities in Henan Province (23ZX006) and Luoyang City Science and Technology Plan Project (2022058Y).

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