Manifestaciones cutáneas comunes de las principales enfermedades hepáticas / Common cutaneous manifestations of major liver diseases

Las enfermedades hepáticas presentan múltiples manifestaciones sistémicas, entre las cuales se destacan los hallazgos en piel, siendo los más comunes el prurito y la ictericia; así mismo, se pueden encontrar angiomas en araña, eritema palmar, xantomas, vasculitis y cambios en anexos. Este artículo tiene como objetivo describir los principales signos y síntomas cutáneos en las enfermedades hepáticas para brindar herramientas semiológicas al clínico en su práctica diaria

Liver disease present multiple systemic manifestations, among which skin findings stand out, being the most common pruritus and jaundice. Other findings can also be manifested like spider angiomas, palmar erythema, xanthomas, vasculitis and changes in skin appendages. The objective of this article is to describe the main skin signs and symptoms of liver diseases to provide semiological tools to the physician in his daily practice.

Efecto del confinamiento por COVID-19 en la prevalencia de la enfermedad hepática esteatósica asociada a disfunción metabólica / Effect of COVID-19 lockdown on the prevalence of metabolic dysfunction-associated steatotic liver disease

Introducción. La enfermedad hepática esteatósica asociada a disfunción metabólica (MASLD) es una condición clínica frecuente, relacionada con el sobrepeso, la dislipidemia y la diabetes. Como estos factores de riesgo están a su vez asociados al sedentarismo y la ganancia de peso, se esperaría un impacto como resultado del confinamiento por COVID-19 en la prevalencia de dicha condición. Metodología. Estudio longitudinal retrospectivo en un panel de datos de 132 pacientes de 2017 a 2022, en donde fueron incluidos pacientes con una ecografía hepática y una valoración médica y paraclínica 1,5 años antes y después del periodo de confinamiento (25 de marzo de 2020 a 28 de febrero de 2021). El desenlace primario fue un cambio significativo en la prevalencia de la MASLD, y se utilizó un modelo exploratorio de regresión logística de efectos fijos con panel de datos para hallar los predictores de cambio. Resultados. En un total de 132 pacientes analizados, la prevalencia global de la MASLD antes (31 %; IC95%: 23-39) y después (35,6 %; IC95%: 27,4-43,8) del confinamiento por COVID-19 no cambió significativamente, sin embargo, en las mujeres sí hubo un aumento significativo (RR: 4; IC95%: 1,0004-16). Se encontró una marcada diferencia de prevalencia entre sexos (17 % en mujeres y 46 % en hombres; p=0,001). El confinamiento se asoció a incrementos en la masa corporal (diferencia: +1 kg; IC95%: 0,1-1,9), el colesterol LDL (diferencia: +9,7 mg/dL; IC95%: 4,9-14,4) y al diagnóstico de prediabetes (RR: 2,1; IC95%: 1,4-3,1). La MASLD se asoció positivamente a la preferencia nutricional por la comida rápida (p=0,047). Solo el índice de masa corporal resultó predictor independiente de MASLD (RR: 1,49; IC95%: 1,07-1,93). Conclusión. La prevalencia global de la MASLD no varió después del confinamiento por COVID-19, pero sí se incrementó en mujeres, y algunos de sus factores de riesgo también aumentaron significativamente. Se encontró equivalencia numérica entre la MASLD y la definición previa de la enfermedad. Se requiere un estudio local más grande para desarrollar y validar un mejor modelo predictor del cambio de la MASLD a través del tiempo.

Introduction. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common clinical condition, related to overweight, dyslipidemia and diabetes. As these risk factors are in turn associated with sedentary lifestyle and weight gain, an impact as a result of the COVID-19 confinement on the prevalence of MASLD would be expected. Methodology. Retrospective longitudinal study in a data panel of 132 patients from 2017 to 2022. Patients with a liver ultrasound and a medical and paraclinical assessment 1.5 years before and after the confinement period (March 25, 2020 to February 28, 2021) were included. The primary outcome was a significant change in the prevalence of MASLD, and an exploratory fixed-effects logistic regression model with panel data was used to find predictors of change. Results. In a total of 132 patients analyzed, the overall prevalence of MASLD before (31%, 95%CI: 23-39) and after (35.6%, 95%CI: 27.4-43.8) confinement by COVID-19 did not change significantly, however, in women there was a significant increase (RR: 4, 95%CI: 1.0004-16). A marked difference in prevalence was found between sexes (17% in women and 46% in men; p=0.001). Confinement was associated with increases in body mass (difference: +1 kg, 95%CI: 0.1-1.9), LDL cholesterol (difference: +9.7 mg/dL, 95%CI: 4.9-14.4) and the diagnosis of prediabetes (RR: 2.1, 95%CI: 1.4-3.1). MASLD was positively associated with nutritional preference for fast food (p=0.047). Only body mass index was an independent predictor of MASLD (RR: 1.49, 95%CI: 1.07-1.93). Conclusion. The overall prevalence of MASLD did not change after the COVID-19 lockdown, but it did increase in women, and some of its risk factors also increased significantly. Numerical equivalence was found between MASLD and the previous definition of the disease. A larger local study is required to develop and validate a better predictor model of MASLD change over time.

Noninvasive Diagnostic Technique for Nonalcoholic Fatty Liver Disease Based on Features of Tongue Images / 中国结合医学杂志

OBJECTIVE@#To investigate a new noninvasive diagnostic model for nonalcoholic fatty liver disease (NAFLD) based on features of tongue images.@*METHODS@#Healthy controls and volunteers confirmed to have NAFLD by liver ultrasound were recruited from China-Japan Friendship Hospital between September 2018 and May 2019, then the anthropometric indexes and sampled tongue images were measured. The tongue images were labeled by features, based on a brief protocol, without knowing any other clinical data, after a series of corrections and data cleaning. The algorithm was trained on images using labels and several anthropometric indexes for inputs, utilizing machine learning technology. Finally, a logistic regression algorithm and a decision tree model were constructed as 2 diagnostic models for NAFLD.@*RESULTS@#A total of 720 subjects were enrolled in this study, including 432 patients with NAFLD and 288 healthy volunteers. Of them, 482 were randomly allocated into the training set and 238 into the validation set. The diagnostic model based on logistic regression exhibited excellent performance: in validation set, it achieved an accuracy of 86.98%, sensitivity of 91.43%, and specificity of 80.61%; with an area under the curve (AUC) of 0.93 [95% confidence interval (CI) 0.68-0.98]. The decision tree model achieved an accuracy of 81.09%, sensitivity of 91.43%, and specificity of 66.33%; with an AUC of 0.89 (95% CI 0.66-0.92) in validation set.@*CONCLUSIONS@#The features of tongue images were associated with NAFLD. Both the 2 diagnostic models, which would be convenient, noninvasive, lightweight, rapid, and inexpensive technical references for early screening, can accurately distinguish NAFLD and are worth further study.

Non-linear association between long-term air pollution exposure and risk of metabolic dysfunction-associated steatotic liver disease

BACKGROUND@#Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) has become a global epidemic, and air pollution has been identified as a potential risk factor. This study aims to investigate the non-linear relationship between ambient air pollution and MASLD prevalence.@*METHOD@#In this cross-sectional study, participants undergoing health checkups were assessed for three-year average air pollution exposure. MASLD diagnosis required hepatic steatosis with at least 1 out of 5 cardiometabolic criteria. A stepwise approach combining data visualization and regression modeling was used to determine the most appropriate link function between each of the six air pollutants and MASLD. A covariate-adjusted six-pollutant model was constructed accordingly.@*RESULTS@#A total of 131,592 participants were included, with 40.6% met the criteria of MASLD. "Threshold link function," "interaction link function," and "restricted cubic spline (RCS) link functions" best-fitted associations between MASLD and PM2.5, PM10/CO, and O3 /SO2/NO2, respectively. In the six-pollutant model, significant positive associations were observed when pollutant concentrations were over: 34.64 µg/m3 for PM2.5, 57.93 µg/m3 for PM10, 56 µg/m3 for O3, below 643.6 µg/m3 for CO, and within 33 and 48 µg/m3 for NO2. The six-pollutant model using these best-fitted link functions demonstrated superior model fitting compared to exposure-categorized model or linear link function model assuming proportionality of odds.@*CONCLUSION@#Non-linear associations were found between air pollutants and MASLD prevalence. PM2.5, PM10, O3, CO, and NO2 exhibited positive associations with MASLD in specific concentration ranges, highlighting the need to consider non-linear relationships in assessing the impact of air pollution on MASLD.

Not only baseline but cumulative exposure of remnant cholesterol predicts the development of nonalcoholic fatty liver disease: a cohort study

BACKGROUND AND AIM@#Remnant cholesterol (remnant-C) mediates the progression of major adverse cardiovascular events. It is unclear whether remnant-C, and particularly cumulative exposure to remnant-C, is associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether remnant-C, not only baseline but cumulative exposure, can be used to independently evaluate the risk of NAFLD.@*METHODS@#This study included 1 cohort totaling 21,958 subjects without NAFLD at baseline who underwent at least 2 repeated health checkups and 1 sub-cohort totaling 2,649 subjects restricted to those individuals with at least 4 examinations and no history of NAFLD until Exam 3. Cumulative remnant-C was calculated as a timeweighted model for each examination multiplied by the time between the 2 examinations divided the whole duration. Cox regression models were performed to estimate the association between baseline and cumulative exposure to remnant-C and incident NAFLD.@*RESULTS@#After multivariable adjustment, compared with the quintile 1 of baseline remnant-C, individuals with higher quintiles demonstrated significantly higher risks for NAFLD (hazard ratio [HR] 1.48, 95%CI 1.31-1.67 for quintile 2; HR 2.07, 95%CI 1.85-2.33 for quintile 3; HR 2.55, 95%CI 2.27-2.88 for quintile 4). Similarly, high cumulative remnant-C quintiles were significantly associated with higher risks for NAFLD (HR 3.43, 95%CI 1.95-6.05 for quintile 2; HR 4.25, 95%CI 2.44-7.40 for quintile 3; HR 6.29, 95%CI 3.59-10.99 for quintile 4), compared with the quintile 1.@*CONCLUSION@#Elevated levels of baseline and cumulative remnant-C were independently associated with incident NAFLD. Monitoring immediate levels and longitudinal trends of remnant-C may need to be emphasized in adults as part of NAFLD prevention strategy.

Association between deacetylase Sirtuins and radiation-induced liver disease / 临床肝胆病杂志

Radiation-induced liver disease （RILD）， also known as radiation hepatitis， is subacute liver injury induced by radiation. As the focus of senescence-related studies， the deacetylase family Sirtuins （SIRTs） have the molecular functions including DNA repair and chromatin regulation， which makes SIRTs a hub for regulating genome and epigenome stability. Radiation-induced hepatic DNA damage and reaction is the primary physiological and pathological process of RILD， which is similar to the function of SIRTs. This article briefly introduces the structure and function of the SIRTs protein family， elaborates on the basic concepts and progress of the physical physiology of radiation therapy， discusses the internal relationship between SIRTs and RILD from the perspective of radiobiology， and points out the possibility of SIRTs as a target for the prevention and treatment of RILD.

Effect of hyodeoxycholic acid on the activity of steatosis hepatocytes and its mechanism / 临床肝胆病杂志

ObjectiveTo investigate the role and mechanism of hyodeoxycholic acid （HDCA） in the progression of metabolic associated fatty liver disease （MAFLD）， and to provide a new theoretical basis for further clarifying the pathogenesis of MAFLD. MethodsL02 hepatocytes were used as experimental cells， and palmitic acid was used to induce steatosis in L02 cells. The farnesoid X receptor （FXR） siRNA interference chain technique was used to construct a hepatocyte cell line with low FXR expression. CCK8 assay was used to observe the effect of HDCA on L02 steatosis hepatocytes at different concentrations （0， 100， 200， 300， and 400 μmol/L） and time points （12， 24， 36， and 48 hours）. The method of qRT-PCR was used to measure the mRNA expression levels of FXR， proliferating cell nuclear antigen （PCNA）， Cyclin D1， phosphatidylinositol 3-kinase （PI3K）， and protein kinase-B （AKT）， and Western blot was used to measure the protein expression levels of FXR， Cyclin D1， PCNA， PI3K， phosphorylated PI3K （p-PI3K）， AKT， and phosphorylated （p-AKT）. A one-way analysis of variance was used for comparison of normally distributed continuous data with homogeneity of variance between multiple groups， and the Tukey HSD test was used for further comparison between two groups； the Welch analysis of variance was used for comparison of normally distributed continuous data with heterogeneity of variance between multiple groups， and the Games-Howell test was used for further comparison between two groups. The independent-samples t test was used for comparison between two groups. ResultsCCK8 assay showed a significant reduction in the viability of L02 cells and steatosis hepatocytes treated by 300 μmol/L HDCA （P<0.05）， and qRT-PCR showed a significant increase in the mRNA expression level of FXR and significant reductions in the mRNA expression levels of PCNA， Cyclin D1， PI3K， and AKT （all P<0.05）. Western blot showed a significant increase in the protein expression level of FRX （P<0.05）， and after interference of FXR expression in L02 cells， there were significant increases in the protein expression levels of PCNA， PI3K， p-PI3K， AKT， and p-AKT （all P<0.05）. ConclusionHDCA inhibits the PI3K/AKT signaling pathway by upregulating FXR expression， thereby inducing a reduction in the viability of steatosis hepatocytes.

Clinical features and serum lipidomic profile of patients with nonalcoholic fatty liver disease and healthy individuals in the overweight population / 临床肝胆病杂志

objectiveTo investigate the differences in clinical indices and lipid metabolism between the patients with nonalcoholic fatty liver disease （NAFLD） and healthy individuals in the overweight population. MethodsIn this study， body mass index （BMI）>23 kg/m2 was defined as overweight. A total of 62 overweight patients with NAFLD who were admitted to Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from August 2020 to April 2021 were enrolled as overweight NAFLD group， and 50 overweight individuals who underwent physical examination during the same period of time were enrolled as control group. Clinical information and blood biochemical parameters were recorded for all subjects. Ultra-performance liquid chromatography-tandem mass spectrometry was used to analyze serum lipidomic profile， and principal component analysis and orthogonal partial least squares-discriminant analysis were used to perform the multivariate statistical analysis of lipidomic data. The chi-square test was used for comparison of categorical data between two groups， and the independent-samples t test or the Wilcoxon rank-sum test was used for comparison of continuous data between two groups. ResultsThe overweight NAFLD group had a significantly higher BMI than the overweight control group （Z=-2.365， P=0.018）. As for serological markers， compared with the overweight control group， the overweight NAFLD group had significantly higher levels of red blood cells， hemoglobin， hematocrit， uric acid， total protein， globulin， alkaline phosphatase， gamma-glutamyl transpeptidase， alanine aminotransferase， aspartate aminotransferase， cholinesterase， low-density lipoprotein， total cholesterol， triglyceride， apolipoprotein B， and blood glucose （all P<0.05）. The lipidomic analysis showed that there was a significant difference in lipid metabolism between the two groups， and a total of 493 differentially expressed lipids were identified （VIP value>1， P<0.05）， among which 143 lipids were significantly upregulated and 350 lipids were significantly downregulated in the overweight NAFLD group. The mean total fatty acid content in the overweight NAFLD group was 3.6 times that in the overweight control group. Compared with the overweight control group， the overweight NAFLD group had a significant reduction in the content of triglyceride with>3 unsaturated bonds （P<0.001） and a significant increase in the content of triglyceride with ≤3 unsaturated bonds （P<0.001）. ConclusionCompared with healthy overweight individuals， overweight NAFLD patients tend to have significant abnormalities in some biochemical parameters and lipid metabolites， with significant increases in the content of fatty acid in blood and the types of saturated fat chains in triglycerides.

Barriers to lifestyle modification in patients with non-alcoholic fatty liver disease: a scoping review / Journal of Rural Medicine

Objective: Non-alcoholic fatty liver disease is common worldwide, and lifestyle modifications are key to its treatment. This study aimed to identify the barriers to lifestyle modifications in patients with non-alcoholic fatty liver disease and to organize the results using the Capability Opportunity Motivation-Behavior (COM-B) model.Materials and Methods: The framework of Arksey and O’ Malley was used in this scoping review. We searched PubMed, Scopus, and the Cochrane Library without language restrictions for reports published up to September 11, 2022, including peer-reviewed literature reporting barriers to lifestyle modifications in patients with non-alcoholic fatty liver disease. Patient-reported barriers were analyzed inductively and organized into the components (capability, opportunity, and motivation) of the COM-B model.Results: The literature search yielded 583 articles, of which seven qualitative studies, four quantitative studies, and one mixed-methods study met the inclusion criteria. Lack of time, lack of information on the diagnosis and management of non-alcoholic fatty liver disease, negative perceptions of the prescribed exercise and diet, physical symptoms interfering with the behavior, presence of comorbidities, and lack of family cooperation were frequently reported as barriers.Conclusion: The results of this study may contribute to the development of appropriate care and education strategies to promote behavioral changes in patients with non-alcoholic fatty liver disease.

The mechanism of action of mitochondrial dysfunction in the development of non-alcoholic fatty liver disease / 临床肝胆病杂志

Nonalcoholic fatty liver disease （NAFLD） has gradually become the main reason affecting human liver health， and many factors are involved in the development and progression of NAFLD. Mitochondria， as the “energy factory” of cells， plays an important role in maintaining normal physiological functions. Studies have shown that hepatic mitochondrial dysfunction promotes the development and progression of NAFLD. This article briefly introduces the latest research advances in the basic characteristics and physiological function of liver mitochondria and reviews new research findings in the association of mitochondrial dysfunction with obesity， simple fatty liver disease， and nonalcoholic steatohepatitis， in order to provide new ideas for the research on targeted mitochondrial therapy for NAFLD.

Role of salidroside in a mouse model of non-alcoholic fatty liver disease： A study based on nicotinamide phosphoribosyltransferase / 临床肝胆病杂志

ObjectiveTo investigate the protective effect of salidroside against nonalcoholic fatty liver disease （NAFLD） and its mechanism of action. MethodsA total of 24 male KM mice were randomly divided into normal group， HFD group， HFD+blank control group， and HFD+salidroside group， with 6 mice in each group. The mice in the normal group were given normal diet， and those in the other groups were given high-fat diet. After 14 weeks of modeling， the mice were given salidroside 100 mg/kg/day by gavage， and related samples were collected at the end of week 22. Enzyme-linked immunosorbent assay was used to measure the serum levels of related biochemical parameters including alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， triglyceride （TG）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C）； HE staining and NAFLD activity score （NAS） were used to observe the liver histopathology of mice； Western blot was used to measure the changes in the expression of NAMPT， Sirt1， AMPKα， and SREBP1 in liver tissue. A one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the normal group， the HFD group had obvious steatosis and extensive large lipid droplets in liver tissue， with significant increases in NAS score （P<0.01） and the content of AST， ALT， TG， TC， and LDL-C in peripheral blood （all P<0.05） and a significant reduction in the content of HDL-C （P<0.05）， as well as significant reductions in the expression levels of NAMPT， AMPKα， and Sirt1 in liver tissue （all P<0.05） and a significant increase in the expression level of SERBP1 （P<0.01）. Compared with the HFD group and the HFD+blank control group， the HFD+salidroside group had reductions in the distribution of vacuolar lipid droplets and intralobular inflammation in liver tissue， alleviation of the ballooning degeneration of hepatocytes， significant reductions in NAS score （P<0.01） and the content of AST， ALT， TG， and LDL-C in peripheral blood （all P<0.05）， and a significant increase in the content of HDL-C （P<0.05）， as well as significant increases in the expression levels of NAMPT， AMPKα， and Sirt1 in liver tissue （all P<0.05） and a significant reduction in the expression level of SERBP1 （P<0.01）. ConclusionSalidroside can significantly improve the pathological state of mice with NAFLD induced by high-fat diet and exert a protective effect against NAFLD by increasing the expression of NAMPT， Sirt1， and AMPKα and reducing the expression of SERBP1.

An excerpt of an international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease （2023） / 临床肝胆病杂志

In 2020， an international expert panel proposed to replace nonalcoholic fatty liver disease with metabolic associated fatty liver disease （MAFLD）. Recent studies have shown that there is a higher risk of chronic kidney disease （CKD） in the MAFLD population and that MAFLD is an independent risk factor for CKD. However， up to now， there are still no guidelines on the prevention and treatment of MAFLD-related CKD. Based on the Delphi method， the authors led a multidisciplinary team of 50 authoritative experts from 26 countries to reach a consensus on some open-ended research issues about the association between MAFLD and CKD， which can help to clarify the important clinical association between MAFLD and the risk of CKD and improve the understanding of the epidemiology， pathogenesis， management， and treatment of MAFLD and CKD， so as to establish a framework for the early prevention and management of these two common and interrelated diseases.

Mechanism of Astragaloside Ⅳ on db/db Mice with Type 2 Diabetes Mellitus and Non-alcoholic Fatty Liver Disease Based on AMPK Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo study the mechanism of astragaloside Ⅳ （AS Ⅳ） on db/db mice with type 2 diabetes mellitus （T2DM） and non-alcoholic fatty liver disease （NAFLD） based on network pharmacology and experimental validation. MethodA total of 24 db/db mice were randomly divided into four groups： model group， metformin group， and low-dose and high-dose AS Ⅳ groups. Six C57 mice were used as the blank group. The low-dose and high-dose AS Ⅳ groups were given AS Ⅳ of 0.015 and 0.030 g·kg-1 by gavage， and the metformin group was given 0.067 g·kg-1 by gavage. The blank and model groups were given equal volumes of distilled water by gavage. After intragastric administration， fasting blood glucose （FBG） was detected， and an oral glucose tolerance test was performed. Serum lipid level and liver histopathology were detected. The target and enrichment pathway of AS Ⅳ for treating T2DM and NAFLD were predicted by network pharmacology， and the main enrichment pathway was verified by molecular biology techniques. The protein expressions of AMPK， p-AMPK， sterol regulatory element-binding protein-1 （SREBP-1）， and fatty acid synthetase （FAS） in liver tissue were detected by Western blot. ResultCompared with the blank group， the levels of body mass， liver weight coefficient， fasting blood glucose， serum total cholesterol， triglyceride， and low-density lipoprotein cholesterol in mice treated with AS Ⅳ were decreased （P<0.05， P<0.01）. The pathology of liver tissue showed significant improvement in lipid accumulation， and imaging results showed that the degree of fatty liver was reduced after AS Ⅳ therapy. Network pharmacological prediction results showed that vascular endothelial growth factor α （VEGFA）， galactoagglutinin 3 （LGALS3）， serine/threonine kinase B2 （Akt2）， RHO-associated coiled-coil protein kinase 1 （ROCK1）， serine/threonine kinase B1 （Akt1）， signaling and transcriptional activator protein （STAT3）， and messtimal epidermal transformation factor （MET） were key targets in "drug-disease" network. The results from the Kyoto encyclopedia of genes and genomes （KEGG） enrichment showed that the AMP-dependent protein kinase （AMPK） signaling pathway was strongly associated with T2DM and NAFLD. Western blot results showed that compared with the blank group， the expression levels of p-AMPK/AMPK in the model group were significantly down-regulated， while those of SREBP-1 and FAS proteins were significantly up-regulated （P<0.01）. Compared with the model group， the expression levels of p-AMPK/AMPK in the metformin group and high-dose AS Ⅳ group were significantly up-regulated， while those of SREBP-1 and FAS proteins were significantly down-regulated （P<0.05， P<0.01）. ConclusionAS Ⅳ regulates the expression of lipid proteins by activating the AMPK signaling pathway， thereby improving lipid metabolism.

Danggui Shaoyaosan Regulates Autophagy via AMPK/mTOR/ULK1 Signaling Pathway in Rat Model of Metabolism-associated Fatty Liver Disease / 中国实验方剂学杂志

ObjectiveTo investigate the regulatory effect of Danggui Shaoyaosan on adenosine monophosphate-activated protein kinase （AMPK）/mammalian target of rapamycin （mTOR）/Unc-51-like kinase-1 （ULK1） signaling pathway in the rat model of metabolism-associated fatty liver disease （MAFLD）. MethodSixty SD rats were randomized into control， model， western medicine （polyene phosphatidylcholine capsules，0.144 g·kg-1）， and low-， medium-， and high-dose （2.44， 4.88， 9.76 g·kg-1， respectively） Danggui Shaoyaosan groups. After being fed with a high-fat diet for 8 weeks， the rats in each group were administrated with corresponding drugs for 4 weeks. At the end of drug treatment， serum and liver tissue were collected for subsequent determination of related indicators. ResultCompared with the control group， the model group showed increased contents of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C） and activities of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） in the serum， increased contents of TC， TG， and free fatty acids （FFAs） in the liver （P<0.01）， and decreased content of high-density lipoprotein cholesterol （HDL-C） in the serum （P<0.01）. Furthermore， the model group showed down-regulated protein levels of p-AMPK， microtubule-associated protein 1 light chain 3B （LC3B） Ⅱ， Beclin1， and ULK1 （P<0.01） and up-regulated protein levels of p-mTOR and ubiquitin-binding protein p62 in the liver （P<0.01）. The hepatic steatosis was obvious and the NAFLD activity score （NAS） and oil red O staining area increased in the model group， （P<0.05， P<0.01）. Compared with the model group， Danggui Shaoyaosan reduced the contents of TC and TG and the activities of ALT and AST in the serum， lowered the levels of TC， TG， and FFA in the liver， down-regulated the protein levels of p-mTOR and p62 （P<0.01）， elevated the serum HDL-C level， and up-regulated the protein levels of p-AMPK， LCBⅡ， Beclin1， and ULK1 in the liver （P<0.05， P<0.01）. Moreover， it alleviated hepatic steatosis and decreased the NAS and oil red O staining area （P<0.05， P<0.01）. ConclusionDanggui Shaoyaosan has therapeutic effect on MAFLD rats by regulating AMPK/mTOR/ULK1 signaling pathway to enhance autophagy.

Mechanism of amino acid metabolism in nonalcoholic fatty liver disease / 临床肝胆病杂志

Nonalcoholic fatty liver disease （NAFLD） is one of the most prevalent chronic liver diseases in the world， affecting about one quarter of the global population， and it is estimated that NAFLD will become the main indication for liver transplantation by 2030. NAFLD can lead to significant abnormalities in the levels of a variety of amino acids including branched-chain amino acids， thereby promoting the development and progression of NAFLD. These results suggest that in addition to glucose and lipid metabolism， amino acid metabolism also plays an important role in the progression of NAFLD. In order to systematically understand the role and mechanism of amino acid metabolism in NAFLD， this article reviews the research advances in amino acid metabolism in NAFLD. This article aims to explore the role and mechanism of amino acid metabolism in the progression of NAFLD， so as to provide ideas and a theoretical basis for clinical prevention and treatment.

Mechanism of action of traditional Chinese medicine in treatment of nonalcoholic fatty liver disease based on intestinal microecology / 临床肝胆病杂志

Nonalcoholic fatty liver disease （NAFLD） is a multisystem disease associated with obesity， insulin resistance， and dyslipidemia and has a complex pathogenesis. Studies have shown that gut microbiota dysbiosis is closely associated with the onset of NAFLD， and traditional Chinese medicine treatment can improve the laboratory markers and clinical symptoms of NAFLD patients by regulating intestinal microbiota and its metabolites. This article elaborates on the association between NAFLD and gut microbiota， the involvement of gut microbiota dysbiosis in the pathogenesis of NAFLD， and the possible mechanism of traditional Chinese medicine treatment in improving NAFLD from the perspective of gut microbiota， in order to provide new ideas for the treatment of NAFLD.

Therapeutic effect of Xiayuxue decoction on a mouse model of nonalcoholic fatty liver disease induced by high-fat diet and its mechanism / 临床肝胆病杂志

ObjectiveTo investigate the mechanism of action of Xiayuxue decoction in inhibiting nonalcoholic fatty liver disease （NAFLD） induced by high-fat diet in mice by regulating nucleotide binding oligomerization domain like receptor containing pyrin domain protein 6 （NLRP6）. MethodsA total of 15 male C57BL/6 mice were randomly divided into low-fat diet （LFD） group， high-fat diet （HFD） group， and Xiayuxue decoction-HFD group （XYXD group）， with 5 mice in each group. Liver function parameters （alanine aminotransferase ［ALT］ and aspartate aminotransferase ［AST］） and blood lipid metabolic indicators （triglycerides ［TG］ and total cholesterol ［TC］） were measured； HE staining and oil red O staining were performed for liver tissue to observe histomorpholoty and lipid droplet deposition； quantitative real-time PCR was used to measure the expression levels of inflammatory factors （tumor necrosis factor-α ［TNF-α］， interleukin-1β ［IL-1β］， interleukin-18 ［IL-18］， and NLRP6） in liver tissue； Western blot was used to measure the protein expression levels of NLRP6， nuclear factor-kappa B （NF-κB）， and NF-κB p65； immunohistochemistry was used to measure the expression of NLRP6 and CD68. Mouse Raw264.7 cells were treated with palmitic acid （PA）， lipopolysaccharide， and serum containing Xiayuxue decoction to observe inflammation. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the LFD group， the HFD group had significant increases in the serum levels of ALT， AST， TC， and TG （all P<0.05）. Liver histopathological examination showed that the HFD group had marked hepatic steatosis and a signficant increase in NAS score （P<0.05）， and quantitative real-time PCR showed significant increases in the inflammatory factors such as IL1β and IL-18 and a significant reduction in the expression of NLRP6 （all P<0.05）. Immunohistochemistry showed that the expression of NLRP6 showed a similar trend as that of the macrophage marker CD68. Western blot showed that after the downregulation of NLRP6 expression， there was a significant increase in phosphorylated NF-κB p65 （P<0.05）. Compared with the HFD group， Xiayuxue decoction effectively improved liver inflammation， upregulated the expression of NLRP6， and downregulated phosphorylated NF-κB p65 in HFD mice （all P<0.05）. After Raw264.7 cells were treated with PA， NLRP6 was downregulated to promote the progression of inflammation （P<0.05）， and treatment with Xiayuxue decoction could upregulate NLRP6 and inhibit inflammation NF-κB （P<0.05）. ConclusionXiayuxue decoction can effectively improve hepatic steatosis and liver inflammation in a mouse model of NAFLD， possibly by regulating NLRP6/NF-κB to alleviate macrophage activation.

Protective effect of Genistein against nonalcoholic fatty liver disease in ovariectomized mice and its mechanism / 临床肝胆病杂志

ObjectiveTo investigate the protective effect of Genistein against nonalcoholic fatty liver disease （NAFLD） in ovariectomized （OVX） mice and its mechanism. MethodsA total of 40 female C57BL/6 mice， aged 6 weeks， were used to establish an OVX mouse model， and then they were randomly divided into blank group， 4-week model group， 6-week model group， 8-week model group， and 10-week model group， with 8 mice in each group. Under the same environmental conditions， the mice were given high-fat diet for modeling， and pathological examination showed that NAFLD was successfully induced by 10-week high-fat diet. Another 40 female C57BL/6 mice， aged 6 weeks， were randomly divided into blank group， sham operation group （Sham group）， OVX group， OVX+L-Genistein （4 mg/kg body weight） group， and OVX+H-Genistein （8 mg/kg body weight） group. The mice in the Sham group were given the same procedure of OVX， without the ligation of the ovarian artery and the resection of the ovary. The mice in the blank group were given normal diet， and those in the other groups were given high-fat diet. Genistein was dissolved in DMSO， and the mice in the Sham group and the OVX group were treated with solvent solution alone by gavage， once a day for 10 consecutive weeks. Body weight and visceral index were recorded， and the mice were sacrificed to collect serum and liver tissue. Kits were used to measure the activity of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） and the serum levels of triglyceride （TG） and total cholesterol （TC）， and HE staining and oil red O staining were used to observe liver histopathology； Western blot was used to measure the protein expression levels of sterol regulatory element-binding protein 1c （SREBP-1c） and peroxisome proliferator-activated receptor alpha （PPARα） associated with lipid metabolism in liver tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the Dunnett-t test was used for further comparison between two groups. ResultsAfter 10 weeks of high-fat diet， the OVX+L-Genistein group and the OVX+H-Genistein group had significantly lower body weight， liver index， and liver tissue weight （all P<0.05）. In addition， Genistein significantly downregulated the serum levels of TC and TG （P<0.05） and reduced the activities of serum AST and ALT （P<0.05）. HE and oil red O staining showed that compared with the OVX group， the OVX+L-Genistein group and the OVX+H-Genistein group had a significant reduction in the accumulation of lipid droplets. Western blot showed that after Genistein intervention， there was a significant reduction in the protein expression level of SREBP-1c and a significant increase in the protein expression level of PPARα （P<0.05）. ConclusionGenistein exerts a protective effect against NAFLD in OVX mice possibly by regulating the expression of SREBP-1c and PPARα， thereby promoting fatty acid oxidation and inhibiting liver lipid synthesis.

Association of polymorphisms of the acetyl-coA acetyltransferase 1 gene and the melatonin receptor 1B gene with the susceptibility to nonalcoholic fatty liver disease / 临床肝胆病杂志

ObjectiveTo investigate the association of the polymorphisms of the acetyl-CoA acetyltransferase 1 （ACAT1） gene and the melatonin receptor 1B （MTNR1B） gene with the susceptibility to nonalcoholic fatty liver disease （NAFLD）. MethodsA total of 164 healthy controls and 228 NAFLD patients were enrolled in this study. PCR and sequencing methods were used to determine the genotypes of the polymorphisms of the ACAT1 gene at the rs1044925 and rs1157651 loci and the MTNR1B gene at the rs10830963 locus， and fasting venous blood samples were collected for biochemical analysis. The t-test was used for comparison of normally distributed continuous data between groups， and the non-parametric Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups； the chi-square test was used for comparison of categorical data between groups. ResultsThere were no significant differences between the NAFLD group and the healthy control group in the genotype distribution of the ACAT1 gene at the rs1044925 and rs1157651 loci and the MTNR1B gene at the rs10830963 locus （all P>0.05）. The carriers of AA genotype at the rs1044925 locus of the ACAT1 gene had a significantly higher level of low-density lipoprotein than the carriers of C allele （Z=-2.08， P=0.04）， and the carriers of G allele at the rs10830963 locus of the MTNR1B gene had a significantly higher level of fasting blood glucose than the carriers of CC genotype （Z=-3.01， P<0.01）. ConclusionThe polymorphisms of the ACAT1 gene at the rs1044925 and rs1157651 loci and the MTNR1B gene at the rs10830963 locus were not associated with the susceptibility to NAFLD. The rs1044925 locus of the ACAT1 gene and the rs10830963 locus of the MTNR1B gene are associated with the levels of low-density lipoprotein and fasting blood glucose， respectively.

Value of Fetuin-A， Fetuin-B， and insulin resistance index in predicting nonalcoholic fatty liver disease / 临床肝胆病杂志

ObjectiveTo investigate the value of serum Fetuin-A and Fetuin-B combined with Homeostasis Model Assessment of Insulin Resistance （HOMA-IR） in predicting nonalcoholic fatty liver disease （NAFLD）. MethodsA total of 120 patients with NAFLD who attended Department of Gastroenterology， The First Affiliated Hospital of Dali University， from June 2020 to June 2021， and 120 healthy individuals who underwent physical examination at Physical Examination Center during the same period of time were enrolled as subjects， and clinical data were collected from all subjects. The serum levels of Fetuin-A and Fetuin-B were measured. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups， and the chi-square test was used for comparison of categorical data between two groups； the multivariate Logistic regression analysis was used to assess the risk factors for NAFLD. The receiver operating characteristic （ROC） curve was plotted to evaluate the predictive efficacy of Fetuin-A and Fetuin-B combined with HOMA-IR in NAFLD patients. ResultsCompared with the healthy control group， the NAFLD group had significantly higher levels of body mass index， systolic blood pressure， diastolic blood pressure， alanine aminotransferase， aspartate aminotransferase， fasting blood glucose， fasting insulin， triglycerides， HOMA-IR， Fetuin-A， and Fetuin-B （all P<0.05）. The multivariate Logistic regression analysis showed that Fetuin-A （odds ratio ［OR］=1.010， 95% confidence interval ［CI］： 1.001‍‍‍ ‍‍‍—‍‍‍ ‍‍1.020， P<0.05）， Fetuin-B （OR=1.113， 95%CI： 1.021‍ ‍‍—‍‍ ‍1.214， P<0.05）， and HOMA-IR （OR=24.053， 95%CI： 2.624‍ ‍‍—‍‍ ‍220.470， P<0.05） were independent risk factors for NAFLD. The ROC curve analysis showed that Fetuin-A， Fetuin-B or HOMA-IR alone had an area under the ROC curve （AUC） of 0.637 （95%CI： 0.551‍ ‍—‍ ‍0.722）， 0.853 （95%CI： 0.796‍ ‍—‍ ‍0.912）， and 0.837 （95%CI： 0.763‍ ‍—‍ ‍0.912）， respectively， and Fetuin-A combined with Fetuin-B， Fetuin-A combined with HOMA-IR， and Fetuin-B combined with HOMA-IR had an AUC of 0.853 （95%CI： 0.795‍ ‍—‍ ‍0.911）， 0.843 （95%CI： 0.770‍ ‍—‍ ‍0.916）， 0.922 （95%CI： 0.877‍ ‍—‍ ‍0.967）， respectively， while the combination of these three indicators had an AUC of 0.922 （95%CI： 0.877‍ ‍—‍ ‍0.966）. ConclusionFetuin-A and Fetuin-B have a certain value in predicting NAFLD， and Fetuin-B combined with HOMA-IR tends to have a higher predictive value.