Down-Regulating the High Level of 17-Beta-Hydroxysteroid Dehydrogenase 13 Plays a Therapeutic Role for Non-Alcoholic Fatty Liver Disease

Wang, Meixi; Li, Jianrui; Li, Hu; Dong, Biao; Jiang, Jing; Liu, Nannan; Tan, Jiali; Wang, Xuekai; Lei, Lei; Li, Hongying; Sun, Han; Tang, Ming; Wang, Huiqiang; Yan, Haiyan; Li, Yuhuan; Jiang, Jian‐Dong; Peng, Zong-Gen

doi:10.3390/ijms23105544

Cited by 16 publications

(13 citation statements)

References 61 publications

(87 reference statements)

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“…66 In a co-culture system, high HSD17B13 expression in hepatocytes indirectly induces HSC activation and downregulation of HSD17B13 in HFD-fed mice is associated with decreased HSC activation. 52 Although speculative, these findings suggest that the protective effect of HSD17B13 lossof-function variants on NAFLD-related liver damage might be partly via reduced HSC activity as a result of HSD17B13's depleted retinol dehydrogenase enzymatic function, which leads to increase in hepatic retinol availability across the liver (Figure 1). This hypothesis needs to be validated and the potential mechanisms of HSD17B13 investigated.…”

Section: Overexpression Of Hsd17b13 In Cultured Hepatocyte Cell Lines...mentioning

confidence: 99%

“…HSD17B13 is newly identified liver‐specific protein that localises to the surface of LDs (Figure 1). Overexpression of HSD17B13 in cultured hepatocyte cell lines leads to the increase in number and size of LDs, 36 potentially by stabilising intracellular TG content 52 . By contrast, enzymatically inactive HSD17B13 variants confer a protective effect against NAFLD progression to NASH.…”

Section: The Role Of Hsd17b13 In the Progression Of Nafldmentioning

confidence: 99%

“…Interestingly, in two murine models, NASH was associated with reduced levels of hepatic retinol and RBP4, with the significant increase in hepatic retinyl ester storage and HSD17B13 expression 66 . In a co‐culture system, high HSD17B13 expression in hepatocytes indirectly induces HSC activation and downregulation of HSD17B13 in HFD‐fed mice is associated with decreased HSC activation 52 . Although speculative, these findings suggest that the protective effect of HSD17B13 loss‐of‐function variants on NAFLD‐related liver damage might be partly via reduced HSC activity as a result of HSD17B13 ’s depleted retinol dehydrogenase enzymatic function, which leads to increase in hepatic retinol availability across the liver (Figure 1).…”

Section: The Role Of Hsd17b13 In the Progression Of Nafldmentioning

confidence: 99%

“…to the increase in number and size of LDs, 36 potentially by stabilising intracellular TG content. 52 By contrast, enzymatically inactive HSD17B13 variants confer a protective effect against NAFLD progression to NASH. However, the physiological function of HSD17B13 and the mechanism by which HSD17B13 variants mediate protection from chronic liver damage remain to be fully elucidated.…”

Section: Overexpression Of Hsd17b13 In Cultured Hepatocyte Cell Lines...mentioning

confidence: 99%

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Review article: the role of HSD17B13 on global epidemiology, natural history, pathogenesis and treatment of NAFLD

Amangurbanova

Huang

Loomba

2022

Aliment Pharmacol Ther

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Background: Non-alcoholic fatty liver disease (NAFLD) occurs in around a quarter of the global population and is one of the leading causes of chronic liver disease. The phenotypic manifestation and the severity of NAFLD are influenced by an interplay of environmental and genetic factors. Recently, several inactivating variants in the novel 17-Beta hydroxysteroid dehydrogenase 13 (HSD17B13) gene have been found to be associated with a reduced risk of chronic liver diseases, including NAFLD. Aims:To review the existing literature on the epidemiology of HSD17B13 and discuss its role in the natural history, disease pathogenesis and treatment of NAFLD. Methods:We extensively searched relevant literature in PubMed, Google Scholar, clini caltr ials.gov and the reference list of articles included in the review.Results: HSD17B13 is a liver-specific, lipid droplet (LD)-associated protein that has enzymatic pathways involving steroids, pro-inflammatory lipid mediators and retinol.The estimated prevalence of the best characterised HSD17B13 variant (rs72613567) ranges from 5% in Africa to 34% in East Asia. Loss-of-function variants in HSD17B13 are protective against the progression of NAFLD from simple steatosis to nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis and hepatocellular carcinoma. Emerging data from mechanistic and preclinical studies with RNA interference (RNAi) and small molecule agents indicate that inhibiting HSD17B13 activity may prevent NAFLD progression. Conclusions:The loss-of-function polymorphisms of the newly identified HSD17B13 gene mitigate the progression of NAFLD. It is important to understand the exact mechanism by which these variants exert a protective effect and implement the gathered knowledge in the treatment of NAFLD.

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Section: Overexpression Of Hsd17b13 In Cultured Hepatocyte Cell Lines...mentioning

confidence: 99%

Section: The Role Of Hsd17b13 In the Progression Of Nafldmentioning

confidence: 99%

Section: The Role Of Hsd17b13 In the Progression Of Nafldmentioning

confidence: 99%

Section: Overexpression Of Hsd17b13 In Cultured Hepatocyte Cell Lines...mentioning

confidence: 99%

See 2 more Smart Citations

Review article: the role of HSD17B13 on global epidemiology, natural history, pathogenesis and treatment of NAFLD

Amangurbanova

Huang

Loomba

2022

Aliment Pharmacol Ther

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“…RNA concentration was determined by NanoDrop 2000 (Thermo Scientific, United States). As previously described (Wang et al, 2022), qRT-PCR was performed with the indicated primers (Table 1) and HiScriptII One Step QRT-PCR SYBR Green Kit (Vazyme, Nanjing, China) using the ABI 7500 Fast system (Applied Biosystems, United States). RNA (30-120 ng) was used as a template, and qRT-PCR amplification consisted of 5 min of reverse transcription step at 50 °C, then 5 min of an initial denaturation step at 95 °C, followed by 40 cycles of PCR at 95 °C for 10 s and 60 °C for 34 s. Target gene expression levels were Frontiers in Pharmacology frontiersin.org normalized to the internal control gene GAPDH using the 2 −ΔΔCT method.…”

Section: Quantitative Real-time Reverse Transcription Polymerase Chai...mentioning

confidence: 99%

Establishment and application of a high-throughput screening model for cell adhesion inhibitors

Sun

Wang

et al. 2023

Front. Pharmacol.

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The cell adhesion between leukocytes and endothelial cells plays an important balanced role in the pathophysiological function, while excessive adhesion caused by etiological agents is associated with the occurrence and development of many acute and chronic diseases. Cell adhesion inhibitors have been shown to have a potential therapeutic effect on these diseases, therefore, efficient and specific inhibitors against cell adhesion are highly desirable. Here, using lipopolysaccharide-induced human umbilical vein endothelial cells (HUVECs) and calcein-AM-labeled human monocytic cell THP-1, we established a high-throughput screening model for cell adhesion inhibitors with excellent model evaluation parameters. Using the drug repurposing strategy, we screened out lifitegrast, a potent cell adhesion inhibitor, which inhibited cell adhesion between HUVEC and THP-1 cells by directly interrupting the adhesion interaction between HUVEC and THP-1 cells and showed a strong therapeutic effect on the mouse acute liver injury induced by poly (I:C)/D-GalN. Therefore, the screening model is suitable for screening and validating cell adhesion inhibitors, which will promote the research and development of inhibitors for the treatment of diseases caused by excessive cell adhesion.

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Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

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Drug development is a long and costly process, with a high degree of uncertainty from the identification of a drug target to its market launch. Targeted drugs supported by human genetic evidence are expected to enter phase II/III clinical trials or be approved for marketing more quickly, speeding up the drug development process. Currently, genetic data and technologies such as genome‐wide association studies (GWAS), whole‐exome sequencing (WES), and whole‐genome sequencing (WGS) have identified and validated many potential molecular targets associated with diseases. This review describes the structure, molecular biology, and drug development of human genetics‐based validated beneficial loss‐of‐function (LOF) mutation targets (target mutations that reduce disease incidence) over the past decade. The feasibility of eight beneficial LOF mutation targets (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, and INHBE) as targets for drug discovery is mainly emphasized, and their research prospects and challenges are discussed. In conclusion, we expect that this review will inspire more researchers to use human genetics and genomics to support the discovery of novel therapeutic drugs and the direction of clinical development, which will contribute to the development of new drug discovery and drug repurposing.

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Down-Regulating the High Level of 17-Beta-Hydroxysteroid Dehydrogenase 13 Plays a Therapeutic Role for Non-Alcoholic Fatty Liver Disease

Cited by 16 publications

References 61 publications

Review article: the role of HSD17B13 on global epidemiology, natural history, pathogenesis and treatment of NAFLD

Review article: the role of HSD17B13 on global epidemiology, natural history, pathogenesis and treatment of NAFLD

Establishment and application of a high-throughput screening model for cell adhesion inhibitors

Drug development advances in human genetics‐based targets

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