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Chronic liver disease (CLD) is a growing global health challenge, accounting for millions of deaths each year. Its major contributors include metabolic dysfunction-associated steatohepatitis (MASH), alcoholic liver disease (ALD), and hepatitis C virus infection. These conditions are closely tied to hepatic steatosis, a condition characterized by the abnormal accumulation of fat in the liver. Recent genome-wide association studies have identified the 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) gene and its loss-of-function variant rs72613567, as a significant protective factor against CLD progression, particularly in MASH and ALD. The review highlights the importance of understanding this gene's function to unravel new therapeutic targets.
Role of HSD17B13 in Liver Disease
HSD17B13, primarily expressed in the liver, is associated with lipid metabolism within hepatic lipid droplets (LDs). The enzyme belongs to a family of proteins that regulate steroid hormone activity and lipid processing. Despite its structural similarities with other dehydrogenases, HSD17B13's primary function lies in modulating liver lipid metabolism. Importantly, the gene is linked to hepatocyte lipid accumulation and, by extension, to conditions like hepatic steatosis. Its loss-of-function mutation, rs72613567, results in a truncated, inactive protein that appears to protect against liver fat buildup and fibrosis, marking it as a key protective factor in CLD.
Genetic Interaction and Disease Progression
The review explores how HSD17B13 variants interact with other genetic factors, such as the PNPLA3 rs738409 mutation, known to elevate CLD risk. Research suggests that the HSD17B13 rs72613567 variant may mitigate the harmful effects of PNPLA3 mutations in liver fibrosis and even reduce the risk of hepatocellular carcinoma (HCC), particularly in MASH and ALD patients. Understanding these genetic interactions provides critical insights into the molecular mechanisms underlying liver disease progression and highlights the complex genetic landscape that modulates disease outcomes.
Protective Effects of HSD17B13 Variants
Several studies reviewed in the article confirm that individuals with the HSD17B13 rs72613567
variant exhibit a reduced risk for both MASH and ALD. For instance, the variant is linked to decreased liver inflammation, lower liver enzyme levels, and reduced progression to cirrhosis and HCC. Interestingly, the protective effects of the variant seem to be more pronounced in populations with traditional risk factors like obesity and alcohol consumption, further suggesting that HSD17B13 modulation may provide significant clinical benefits.
Implications for Hepatocellular Carcinoma (HCC)
The review delves into the potential role of HSD17B13 in the development of HCC. Studies have demonstrated that lower levels of HSD17B13 expression are associated with poor HCC outcomes. The gene's downregulation in liver cancer tissues contrasts with its protective effects in chronic liver conditions, suggesting a complex and context-dependent role in liver disease. The presence of the HSD17B13 variant correlates with better survival rates and reduced HCC incidence, emphasizing its potential utility in predictive genetic models for cancer risk.
Therapeutic Potential
The inhibition of HSD17B13, particularly in patients with metabolic liver disease, represents a promising therapeutic avenue. The article discusses ongoing research into RNA interference and small molecule inhibitors targeting HSD17B13, both of which have shown potential in reducing liver damage markers in experimental models. This approach could lead to the development of new treatments for MASH and ALD, particularly for individuals carrying the protective genetic variant.
Conclusions
This review underscores the significant role that HSD17B13 and its genetic variants play in CLD progression and protection. By reducing hepatic lipid accumulation and inflammation, the HSD17B13 rs72613567 variant offers a protective effect against liver fibrosis and HCC. Future research should focus on fully elucidating the molecular mechanisms behind these protective effects, with the goal of developing targeted therapies that could mitigate the global burden of CLD.
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https://www.xiahepublishing.com/2310-8819/JCTH-2024-00257
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
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