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

Wang, Mei-xi; Li, Jianrui; Li, Hu; Dong, Biao; Jiang, Jin; Liu, Nannan; Tan, Jia-li; Wang, Xue-kai; Lei, Lei; Li, Hongying; Sun, Han; Tang, Ming; Wang, Huiqiang; Yan, Haiyan; Li, Yuhuan; Jiang, Jian‐Dong; Peng, Zong-Gen

doi:10.2139/ssrn.4065600

Cited by 3 publications

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…progression to MASH (6,7,(36)(37)(38). In agreement with our in vivo data, mouse models have shown that inhibition/knockdown of Hsd17b13 protects against both hepatic triglyceride accumulation and fibrosis (27,39,40) . We determined that shHsd17b13 knockdown repressed hepatic fatty acid transporter Cd36 expression in mice and reciprocally, increased Hsd17b13 expression in cells led to increased Cd36 expression.…”

Section: Discussionsupporting

confidence: 89%

Hydroxysteroid 17-beta dehydrogenase 13(Hsd17b13)knockdown attenuates liver steatosis in high-fat diet obese mice

Mahmood,

Morrice,

Thompson

et al. 2024

Preprint

View full text Add to dashboard Cite

Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) loss-of-function gene variants are associated with decreased risk of 'metabolic dysfunction-associated steatotic liver disease' (MASLD). Our RNA-seq analysis of steatotic liver from obese mice -/+ Fenretinide treatment identified major beneficial effects of Fenretinide on hepatic gene expression includingHsd17b13. We sought to determine the relationship between Hsd17b13 expression and MASLD and to validate it as a therapeutic target by liver-specific knockdown.Hsd17b13expression, which is unique to hepatocytes and associated with the lipid-droplet, was elevated in multiple models of MASLD and normalised with prevention of obesity and steatotic liver. Direct, liver-specific, shRNA-mediated knockdown ofHsd17b13(shHsd17b13) in high-fat diet (HFD)-obese mice, markedly improved hepatic steatosis with no effect on body weight, adiposity or glycaemia. shHsd17b13 decreased elevated serum ALT, serum FGF21 levels and markers of liver fibrosis e.g.Timp2. shHsd17b13 knockdown in HFD-obese mice and Hsd17b13 overexpression in cells reciprocally regulated expression of lipid metabolism genes e.g.Cd36. Global lipidomic analysis of liver tissue revealed a major decrease in diacylglycerols (e.g. DAG 34:3) with shHsd17b13 and an increase in phosphatidylcholines containing polyunsaturated fatty acids (PUFA) e.g. PC 34:3 and PC 42:10. Expression of key genes involved in phospholipid and PUFA metabolism e.g.Cept1, were also reciprocally regulated suggesting a potential mechanism of Hsd17b13 biological function and role in MASLD. In conclusion,Hsd17b13knockdown in HFD-obese adult mice was able to alleviate MASLD via regulation of fatty acid and phospholipid metabolism, thereby confirming HSD17B13 as a genuine therapeutic target for MASLD and development of liver fibrosis.

show abstract

Section: Discussionsupporting

confidence: 89%

Hydroxysteroid 17-beta dehydrogenase 13(Hsd17b13)knockdown attenuates liver steatosis in high-fat diet obese mice

Mahmood,

Morrice,

Thompson

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

The Influence of Sex Hormones in Liver Function and Disease

Kasarinaite

Sinton

Saunders

et al. 2023

Cells

View full text Add to dashboard Cite

The liver performs a multitude of bodily functions, whilst retaining the ability to regenerate damaged tissue. In this review, we discuss sex steroid biology, regulation of mammalian liver physiology and the development of new model systems to improve our understanding of liver biology in health and disease. A major risk factor for the development of liver disease is hepatic fibrosis. Key drivers of this process are metabolic dysfunction and pathologic activation of the immune system. Although non-alcoholic fatty liver disease (NAFLD) is largely regarded as benign, it does progress to non-alcoholic steatohepatitis in a subset of patients, increasing their risk of developing cirrhosis and hepatocellular carcinoma. NAFLD susceptibility varies across the population, with obesity and insulin resistance playing a strong role in the disease development. Additionally, sex and age have been identified as important risk factors. In addition to the regulation of liver biochemistry, sex hormones also regulate the immune system, with sexual dimorphism described for both innate and adaptive immune responses. Therefore, sex differences in liver metabolism, immunity and their interplay are important factors to consider when designing, studying and developing therapeutic strategies to treat human liver disease. The purpose of this review is to provide the reader with a general overview of sex steroid biology and their regulation of mammalian liver physiology.

show abstract

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1

Jiang,

Li,

Tang

et al. 2024

IJMS

Self Cite

View full text Add to dashboard Cite

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.

show abstract

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

Cited by 3 publications

References 0 publications

Hydroxysteroid 17-beta dehydrogenase 13(Hsd17b13)knockdown attenuates liver steatosis in high-fat diet obese mice

Hydroxysteroid 17-beta dehydrogenase 13(Hsd17b13)knockdown attenuates liver steatosis in high-fat diet obese mice

The Influence of Sex Hormones in Liver Function and Disease

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1

Contact Info

Product

Resources

About