Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13

Abstract

Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports that predicted loss of function variants in HSD17B13 protect against the progression of steatosis to non-alcoholic steatohepatitis with fibrosis and hepatocellular carcinoma. Here we report crystal structures of full length HSD17B13 in complex with its NAD+ cofactor, and with lipid/detergent molecules and small molecule inhibitors from two distinct series in the ligand binding pocket. These structures provide insights into a mechanism for lipid droplet-associated proteins anchoring to membranes as well as a basis for HSD17B13 variants disrupting function. Two series of inhibitors interact with the active site residues and the bound cofactor similarly, yet they occupy different paths leading to the active site. These structures provide ideas for structure-based design of inhibitors that may be used in the treatment of liver disease.

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

“…Thus, it is not clear if this signalling network can be delineated sufficiently to facilitate targeting for the treatment of metabolic diseases. Recently, the X-ray crystal structure of Hsd17b13 has provided insights into a mechanism for association with the lipid droplet and interaction with ATGL or other potential binding partners (30). The findings suggest that HSD17B13 may have an important scaffold function at the lipid droplet.…”

Drug development advances in human genetics‐based targets

“…202 It consists of six structural domains: hydrophobic domain (HD), PAT-like structural domain, cofactor-binding structural domain (CFB), folding/dimerization structural domain (F/D), catalytic structural domain (CAT), and stability/unknown structural domain (S/U). [203][204][205] HSD17B13 is highly expressed mainly in mouse and human liver. In addition, human HSD17B13 has been identified as a retinol dehydrogenase (RDH), 206,207 which catalyzes the conversion of retinol to retinaldehyde in combination with appropriate LD targeting and cofactors and is the rate-limiting enzyme controlling the biosynthesis of trans-retinoic acid during NAFLD progression.…”

“…17‐β‐Hydroxysteroid dehydrogenase 13 (HSD17B13) is a hydroxysteroid dehydrogenase that catalyzes the conversion between 17‐keto and 17‐hydroxysteroids 202 . It consists of six structural domains: hydrophobic domain (HD), PAT‐like structural domain, cofactor‐binding structural domain (CFB), folding/dimerization structural domain (F/D), catalytic structural domain (CAT), and stability/unknown structural domain (S/U) 203–205 . HSD17B13 is highly expressed mainly in mouse and human liver.…”

Review article: Hepatic steatosis and its associations with acute and chronic liver diseases

“…LD‐associated proteins comprise a diverse group of 100–150 proteins, 74 whose relevance in protection against and development of hepatic steatosis is becoming steadily more appreciated. Trafficking of LD‐associated proteins is not well understood 75 ; targeting of caveolin protein to LDs involves a hydrophobic domain and N‐terminally adjacent basic residues, 76 while an amphiphatic helix and angulation induced by proline residues may help 17‐beta‐hydroxysteroid dehydrogenase 13 segregate preferentially into the phospholipid monolayer of LDs 77 . The incorporation of amphiphatic helices into LDs, where intramembrane domains likely provide surfactant activity, has been suggested by Chorlay and Thiam 78 to be dependent on the neutral lipid content of the LD.…”