HSD17B13 has recently emerged as a gene of interest in human health. It encodes an enzyme that plays a role in various metabolic processes within the body. Research has highlighted its connection to several health conditions, particularly those affecting the liver. Understanding its enzymatic activity has opened new avenues for exploring disease mechanisms and potential therapies.
Understanding HSD17B13
HSD17B13, or hydroxysteroid 17-beta dehydrogenase 13, is a gene that encodes an enzyme belonging to the 17β-hydroxysteroid dehydrogenase family. This family of enzymes is involved in the metabolism of steroids (including sex hormones), fatty acids, cholesterol, and retinoids. HSD17B13 was first isolated in 2007 from a human liver cDNA library.
The HSD17B13 enzyme is predominantly expressed in the liver, associated with lipid droplets (LDs). Lipid droplets are cellular storage sites for lipids, such as triglycerides, and manage cellular energy resources. Overexpression of HSD17B13 in cultured liver cells can lead to an increase in the number and size of these lipid droplets by stabilizing triglycerides within cells. Its enzymatic function includes the conversion of retinol to retinaldehyde.
HSD17B13 and Liver Disease Progression
HSD17B13 has an association with the progression of liver diseases, particularly non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). NAFLD is characterized by fat accumulation in the liver, while NASH involves inflammation and liver cell damage in addition to fat. Research indicates that HSD17B13 expression is elevated in individuals with NAFLD compared to healthy individuals.
A commonly studied genetic variant in the HSD17B13 gene, known as rs72613567:TA (or the TA allele), influences liver disease risk. This variant involves an insertion of an adenine nucleotide near a splice site in exon 6, which disrupts messenger RNA (mRNA) splicing. This disruption leads to the production of a shortened and less stable protein, resulting in a loss of enzyme function.
The rs72613567:TA variant is protective against the progression of NAFLD to more severe forms, such as NASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma. For instance, the TA allele has been linked to a 30% reduced risk for NAFLD and a 49% reduced risk for nonalcoholic cirrhosis in homozygotes. This protective effect extends to reducing inflammation and ballooning of liver cells, which are histological features of NASH.
The mechanism behind this protective effect is linked to the loss of HSD17B13 enzymatic activity from the rs72613567:TA variant. One proposed mechanism suggests that the wild-type HSD17B13 enzyme, which converts retinol to retinaldehyde, contributes to increased lipogenesis in the liver. Therefore, a loss of this enzymatic activity due to the variant could lead to less lipid accumulation and reduced liver damage. The variant’s protective effect may also be influenced by other genetic factors, such as the PNPLA3 rs738409 genotype, and clinical factors like age, sex, obesity, and diabetes.
HSD17B13 as a Therapeutic Target
Understanding HSD17B13’s role in liver disease progression has opened avenues for drug development, particularly for NAFLD and NASH. Since loss-of-function variants of HSD17B13 are associated with protection against severe liver disease, inhibiting the enzyme’s activity in individuals with the functional gene is a promising therapeutic strategy. This approach aims to mimic the protective effect observed in individuals with the genetic variant.
Current research directions include the development of HSD17B13 inhibitors, which are compounds designed to block the enzyme’s activity. Several novel inhibitors are being investigated, with some showing promise in preclinical studies. For example, the selective HSD17B13 inhibitor BI-3231 has been shown to reduce triglyceride accumulation in liver cells and improve lipid homeostasis in laboratory models of lipotoxicity.
Targeting HSD17B13 could prevent or even reverse liver damage in patients with NAFLD and NASH. By reducing the enzyme’s activity, these inhibitors could decrease lipid accumulation, inflammation, and fibrosis in the liver, slowing or halting disease progression. The development of these inhibitors represents a step towards personalized treatments for chronic liver diseases, offering a new therapeutic option.