Gehua Jiejiu Dizhi decoction (葛花解酒涤脂汤) ameliorates alcoholic fatty liver in mice by regulating lipid and bile acid metabolism and with exertion of antioxidant stress based on 4DLabel-free quantitative proteomic study

doi:10.19852/j.cnki.jtcm.20231018.001

Abstract

Abstract:

OBJECTIVE: To analyze the effect and molecular mechanism of Gehua Jiejiu Dizhi decoction (葛花解酒涤脂汤, GJDD) on alcoholic fatty live disease (AFLD) by using proteomic methods.

METHODS: The male C57BL/6J mouse were randomly divided into four groups: control group, model group, GJDD group and resveratrol group. After the AFLD model was successfully prepared by intragastric administration of alcohol once on the basis of the Lieber-DeCarli classical method, the GJDD group and resveratrol group were intragastrically administered with GJDD (4900 mg/kg) and resveratrol (400 mg/kg) respectively, once a day for 9 d. The fat deposition of liver tissue was observed and evaluated by oil red O (ORO) staining. 4DLabel-free quantitative proteome method was used to determine and quantify the protein expression in liver tissue of each experimental group. The differentially expressed proteins were screened according to protein expression differential multiples, and then analyzed by Gene ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Finally, expression validation of the differentially co-expressed proteins from control group, model group and GJDD group were verified by targeted proteomics quantification techniques.

RESULTS: In semiquantitative analyses of ORO, all kinds of steatosis (ToS, MaS, and MiS) were evaluated higher in AFLD mice compared to those in GJDD or resveratrol-treated mice. 4DLabel-free proteomics analysis results showed that a total of 4513 proteins were identified, of which 3763 proteins were quantified and 946 differentially expressed proteins were screened. Compared with the control group, 145 proteins were up-regulated and 148 proteins were down-regulated in the liver tissue of model group. In addition, compared with the model group, 92 proteins were up-regulated and 135 proteins were down-regulated in the liver tissue of the GJDD group. 15 differentially co-expressed proteins were found between every two groups (model group vs control group, GJDD group vs model group and GJDD group vs control group), which were involved in many biological processes. Among them, 11 differentially co-expressed key proteins (Aox3, H1-5, Fabp5, Ces3a, Nudt7, Serpinb1a, Fkbp11, Rpl22l1, Keg1, Acss2 and Slco1a1) were further identified by targeted proteomic quantitative technology and their expression patterns were consistent with the results of 4D label-free proteomic analysis.

CONCLUSIONS: Our study provided proteomics-based evidence that GJDD alleviated AFLD by modulating liver protein expression, likely through the modulation of lipid metabolism, bile acid metabolism and with exertion of antioxidant stress.

Key words: fatty liver, alcoholic, 4DLabel-free quantitative proteome, targeted protein quantification, Gehua Jiejiu Dizhi decoction

HAN Min, YI Xu, YOU Shaowei, WU Xueli, WANG Shuoshi, HE Diancheng. Gehua Jiejiu Dizhi decoction (葛花解酒涤脂汤) ameliorates alcoholic fatty liver in mice by regulating lipid and bile acid metabolism and with exertion of antioxidant stress based on 4DLabel-free quantitative proteomic study[J]. Journal of Traditional Chinese Medicine, 2024, 44(2): 277-288.

Figures/Tables 6

Figure 1 Hepatic steatosis of liver in 4 groups of mice by ORO staining (× 100 magnification) A: control group:treated only withfree drinking water; B: AFLD model group:treated with ethanol and drinking water (2.6 g/kg); C: GJDD intervention group: treated with GJDD of 4.9 g/kg; D: resveratrol intervention group: treated with resveratrol of 4 g/kg. Diffuse and red dropwise lipid vacuoles were found in the AFLD mice liver tissue, but they were significantly reduced both in GJDD and resveratrol-treated mice, accompanied by small drops, especially in the GJDD group. Semiquantitative analysis of fatty degeneration showed that AFLD mice were mainly MiS, and the moderate MaS was observed also in 32.2% of mice. Correspondingly, GJDD group and resveratrol group showed a small amount of MiS and no MaS. Black arrow indicates large steatosis in model group, but not in other groups (× 200 magnification). ORO: oil red o; MaS: macrovesicular steatosis; MiS: microvesicular steatosis.

Table 1 Results of semiquantitative analysis of liver steatosis by ORO staining in each group ( ± s)

Group	n	MaS (%)			MiS (%)	ToS (%)
Group	n	Mild	Moderate	Severe	MiS (%)	ToS (%)
Control	8	0	0	0	2.0±1.2	2.0±1.2
Model	8	10.0±2.5^a	32.4±6.5^a	0	36.3±7.6^a	68.8±10.4^a
GJDD	8	0.9±1.2	0.3±6.0	0	5.0±2.6^b	7.2±2.7^b
Resveratrol	8	0.9±2.3	0.3±4.0	0	10.3±2.7^b	18.6±3.2^b

Figure 2 Volcano plots showed the differentially protein expression in every two groups (M/C, P/M, R/M) A: AFLD group/Control group (M/C); B: GJDD group/AFLD group (P/M); C: resveratrol group/AFLD group (R/M). Control group: treated only with free drinking water; AFLD model group: treated with ethanol and drinking water (2.6 g/kg); GJDD intervention group: treated with GJDD of 4.9 g/kg; resveratrol intervention group: treated with resveratrol of 4 g/kg. AFLD: alcoholic fatty live disease; GJDD: Gehua Jiejiu Dizhi decoction. The ratio of the mean value of repeated quantitative value of protein in the comparison sample pair was taken as the fold change. The relative quantitative value of protein in the comparison sample pair was tested by t-test. The specified thresholds include log2 fold change and adjusted P-value after log conversion, which were used to measure the fold and significance of protein expression differences respectively. In the figure, positive and red dots indicated that the difference was up-regulated. On the contrary, negative and green dots indicated that the difference was down-regulated.

Figure 3 Bubble plot of KEGG pathway enrichment analysis of proteins with differential expression level A: AFLD group/Control group; B: GJDD group/AFLD group; C: resveratrol group/AFLD group. Control group: treated only with free drinking water; AFLD model group: treated with ethanol and drinking water (2.6 g/kg); GJDD intervention group: treated with GJDD of 4.9 g/kg; resveratrol intervention group: treated with resveratrol of 4 g/kg. X-axis represents enrichment factor. Y-axis represents pathway name. The darker the mapping color, the smaller the P-value and the more obvious the significance, the larger the mapping value and the more enrichment. The same KEGG enrichment pathway involved in the differential proteins of M/C, P/M, and R/M comparison groups are boxed in three colors respectively, in which red is “retinol metabolism”, purple is “pyruvate metabolism”, and blue is “steroid hormone biosynthesis”. KEGG: Kyoto Encyclopedia of Genes and Genomes; AFLD: alcoholic fatty live disease; GJDD: Gehua Jiejiu Dizhi decoction.

Table 2 Differential co-expressed proteins in groups of C, M and P

Proteins accession	Protein description/ Gene	MW (kDa)	Coverage (%)	Unique peptides	Ratio
Proteins accession	Protein description/ Gene	MW (kDa)	Coverage (%)	Unique peptides	M/C	P/C	P/M
P43275	Histone H1.1/ H1-1	21.79	31.9	4	6.54	2.81	0.43
P43276	Histone H1.5/ H1-5	22.58	25.1	4	6.48	2.37	0.37
Q9WUD1	STIP1 homology and U box-containing protein/ Stub1	34.91	34.2	9	5.66	2.55	0.45
Q9D7S7	60S ribosomal protein L22-like 1/ Rpl22l1	14.47	45.1	4	5.08	2.30	0.45
Q9D1M7	Peptidyl-prolyl cis-trans isomerase/ Fkbp11	22.14	41.3	5	4.91	1.85	0.38
G3X982	Aldehyde oxidase 3/ Aox3	146.9	55.4	52	0.46	3.60	7.9
Q99P30	Peroxisomal coenzyme A/ Nudt7	26.86	51.7	14	0.45	3.11	6.9
Q9DCY0	Glycine N-acyltransfera se-like protein/ Keg1	33.72	55.3	13	0.40	2.53	6.28
Q63880	Carboxylesterase 3A/Ces3a	63.32	52.7	11	0.20	2.68	13.17
Q05816	Fattyacid-bindingprotein 5/ Fabp5	15.14	72.6	9	0.19	0.50	2.66
Q9QXG4	Acetyl-coenzyme A synthe tase/ Acss2	78.86	43.2	25	0.19	0.48	2.48
P11589	Major urinary protein 2/ Mup2	20.66	78.3	3	0.14	2.94	21.74
Q9QXZ6	Solute carrier organican ion transporter family member/ Slco1a1	74.40	32.1	16	0.11	5.21	45.54
P11588	Major urinary protein 1/ Mup1	20.65	81.1	3	0.09	5.46	63.4
Q9D154	Leukocyte elastase inhibitor A/ Serpinb1a	42.58	35.4	12	0.08	0.26	3.11

Table 3 Differentially co-expressed proteins confirmed by targeted quantitative proteomics based on mass spectrometry

Proteins accession	Proteins description	Gene	Peptides	Ratio
Proteins accession	Proteins description	Gene	Peptides	M/C	P/C	P/M
Q63880	Carboxylesterase 3A	Ces3a	LGIFGFLSTGDK	0.15	3.08	19.87
Q05816	Fatty acid-binding protein 5	Fabp5	ELGVGLALR	0.21	0.54	2.58
Q9D154	Leukocyte elastase inhibitor A	Serpinb1a	FQSLNAEVSK	0.21	0.37	1.78
Q9QXG4	Acetyl-coenzyme A synthetase	Acss2	TACPGPFLQYNFDVTK	0.21	0.33	1.60
Q9QXZ6	Solute carrier organicanion transporter family member	Slco1a1	GVQHPLYGEK	0.44	10.53	23.69
Q9DCY0	Glycine N-acyltransferase-like protein	Keg1	VIESLGATNLGK	0.51	3.16	6.20
G3X982	Aldehyde oxidase 3	Aox3	TTWIAPGTLNDLLELK	0.56	3.80	6.79
Q99P30	Peroxisomal coenzyme A	Nudt7	EVFFVPLDYFLHPQVYYQK	0.56	3.62	6.45
Q9D7S7	60S ribosomal protein L22-like 1	Rpl22l1	TGNLGNVVHIER	12.31	3.16	0.26
P43276	Histone H1.5	H1-5	GGVSLPALK	8.06	2.71	0.34
Q9D1M7	Peptidyl-prolyl cis-trans isomerase	Fkbp11	DPLVIELGQK	6.74	2.34	0.35

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