目的 评估过去30年，204个国家和地区非酒精性脂肪性肝病（NAFLD）伤残调整生命年（DALYs）的变化趋势，以及年龄-时期-队列效应。方法 所有数据来源于全球疾病负担研究（GBD）数据。针对1990—2019年204个国家和地区NAFLD的DALYs趋势进行分析，采用折点回归模型评估年龄标化DALYs率年均百分比变化（APC）；同时，利用年龄-时期-队列模型评估年龄、时期及出生队列对NAFLD的DALYs的影响。结果 1990—2019年，NAFLD的DALYs总量增加了62.92%，全人群DALYs率（每10万人）也增加了12.65%，而年龄标化DALYs率则由1990年的63.28（95%UI：48.58，80.86）下降至2019年的53.33（95%UI：40.73，68.29），降幅约为15.72%。全球范围内，APC模型估算的DALYs净漂移为每年-0.88%（95%CI：-0.91~ -0.85）。无论是DALYs总量、全人群DALYs率还是年龄标化DALYs率，其在女性和男性中的变化趋势与总体趋势一致。尽管全球及按社会人口学指数（SDI）分组的5个区域中，≥80岁人群的DALYs时间趋势逐步上升，但仅高SDI区域的上升趋势较为明显。折点回归分析显示，1990—2019年，年龄标化DALYs率呈现“先缓慢上升、后下降、再上升、最终下降”的波动趋势，总体为下降趋势，1990—2019年平均APC为-0.58%。年龄-时期-队列模型表明，全球、各区域及国家均存在不利的年龄效应，而时期效应与出生队列效应在不同区域总体呈有利趋势，但也存在一定差异。结论 1990—2019年，全球NAFLD的DALYs总量和全人群DALYs率上升，而年龄标化DALYs率总体下降，高SDI地区老年人负担上升更明显。年龄-时期-队列分析显示全球普遍存在不利的年龄效应，时期和出生队列效应总体有利但区域差异显著。

      Objective To evaluate the trends in the disability-adjusted life years（DALYs）of nonalcoholic fatty liver disease（NAFLD）and the effects of age-period-cohort in 204 countries and regions in the past 30 years．Methods All data were obtained from the Global Burden of Disease Study 2019．Trends in DALYS for NAFLD were assessed in 204 countries and territories from 1990 to 2019，and trends in the annual percentage change（APC）of age-standardized DALY rate were assessed by a joinpoint regression model．And age-period-cohort models were used to assess the effects of age-period-cohort on DALYs for NAFLD．Results From 1990 to 2019，the number of DALYs due to NAFLD increased by 62.92%，and all-age DALY rate per 100，000 population also increased by 12.65%，while the age-standardized DALY rate decreased from 63.28（48.58，80.86）in 1990 to 53.33（40.73，68.29）in 2019，a decrease of about 15.72%．Globally，the APC model estimated a net drift for DALYs of -0.88%（95%CI：-0.91，-0.85）per year，and for the number of DALYs，all-age DALYs rate，age-standardized DALY rate and net drift in female and male，the change trend of all regions over the past 30 years were consistent with the total population．Although the time trend of NAFLD DALYs among people over 80 years old was gradually rising in the world and five regions grouped according to socio‐demographic index（SDI），only the high SDI region had a more obvious time trend．Globally，the joinpoint regression analysis showed the age-standardized DALY rate appeared a trend of first gradually upward and then downward and then upward and finally downward during 1990-2019．Overall there was a downward trend，with an average APC of -0.58 during 1990 to 2019．Age-period-cohort model showed that unfavourable age effects were found in the world，all regions and countries，while the period and birth cohorts effects in different regions were favorable，but there were also some differences．Conclusions From 1990 to 2019，the global DALYs and all-age DALY rates of NAFLD increased，whereas the age-standardized DALY rate showed an overall decline，with a more pronounced burden among older adults in high-SDI regions．The age-period-cohort analysis revealed unfavorable age effects worldwide，while period and birth cohort effects were generally favorable but varied considerably across regions．

非酒精性脂肪性肝病(NAFLD)是世界范围内慢性肝病的一个主要原因,约15%的NAFLD患者会发展为非酒精性脂肪性肝炎、肝纤维化、肝硬化甚至肝癌。目前其发病及进展机制尚未明确,也无有效治疗手段。因此,构建临床前NAFLD动物模型至关重要,有助于为NAFLD提供临床治疗的新方案。本文将系统分析目前已构建的NAFLD动物模型在临床前研究中的局限性,并重点总结和综述基于基因编辑在NAFLD动物模型构建中的应用及研究进展,这对于探讨NAFLD发病机制及新药研发具有重要的临床意义。

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, and about 15% of NAFLD patients will develop into nonalcoholic steatohepatitis, hepatic fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. However, the biological mechanism of the pathogenesis and progression of NAFLD is not fully understood, and there are still no effective or targeted therapies for NAFLD. Therefore, it is an urgent need to construct pre-clinical animal models of NAFLD, which will help to better understand and explore the potential therapeutic strategy in the treatment of NAFLD. Here, we summarize the recent advances and limitations of the established animal models of NAFLD and focus on the potential application and research progress of genome editing for constructing the animal models of NAFLD. There animal models will be very useful to reveal the pathologic mechanism of human NAFLD, and to screen new therapeutic drugs.

目的 通过生物信息分析途径,从分子水平揭示非酒精性脂肪性肝病（NAFLD）的发病发展机制,为NAFLD研究提供新的思路。方法 从公共数据库GEO中下载NAFLD相关的基因芯片数据GSE48452,利用Transcriptome Analysis Console软件筛选差异表达基因,FunRich软件和STRING在线分析工具对差异基因进行下一步的生物信息学分析。结果 正常组与NAFLD组差异基因52个,正常组与非酒精性脂肪性肝炎（NASH）基因64个,共同差异基因15个。这些差异表达基因参与脂质转运、胆汁酸合成、脂质和脂蛋白代谢、生物氧化等过程。通过通路分析及蛋白质相互作用分析进一步筛选出与NAFLD发病发展密切相关的18个差异表达基因。结论 通过生物信息学分析筛选出MSN、CDC45、ANXA5、PIK3CG和DTL基因可能为研究乃至阻断NAFLD发展进程的重要靶点,需进一步验证。

Objective To explore the molecular mechanism of nonalcoholic fatty liver disease （NAFLD） with bioinformatics analysis. Methods The microarray data of NAFLD were downloaded from the Gene Expression Omnibus （GEO） database and analyzed using Transcriptome Analysis Console （TAC） for screening differentially expressed genes. The further analysis of differentially expressed genes was conducted by FunRich software and the online tool STRING. Results For the comparison of control group vs. NAFLD group,52 genes have differentially expressed,while control groups vs. nonalcoholic steatohepatitis （NASH） group,64 genes have differentially expressed. 15 differentially expressed genes were found in both comparisons. These genes were involved in the biological pathway of lipid transport,bile acid biosynthesis,metabolism of lipids and lipoproteins and biological oxidations. With biological pathway analysis and protein-protein interaction analysis,18 differentially expressed genes were found closely associated with the progression of NAFLD. Conclusion MSN、CDC45、ANXA5、PIK3CG and DTL may be the important target for study the progression of NAFLD,which needs a further study to confirm.