HSD17B13

HSD17B13 (hydroxysteroid 17-beta dehydrogenase 13, formerly designated short-chain dehydrogenase/reductase family 9, SCDR9) is a hepatocyte-specific, lipid-droplet-associated enzyme encoded by the HSD17B13 gene on human chromosome 4q22.1 (7 exons, 300 amino acids, ~34 kDa monomer) belonging to the nicotinamide adenine dinucleotide (NAD⁺)-dependent short-chain dehydrogenase/reductase (SDR) superfamily. Expressed predominantly on the phospholipid monolayer coat of hepatocyte cytoplasmic lipid droplets (LDs), HSD17B13 catalyzes the oxidation of all-trans-retinol (vitamin A) to all-trans-retinaldehyde, alongside the conversion of 17β-estradiol, pro-inflammatory bioactive eicosanoids (such as leukotriene B₄, LTB₄, and 13-S-hydroxyoctadecadienoic acid), and pyrimidine catabolites (dihydrothymine/dihydrouracil modulation via scaffold interactions).

In 2018, exome-wide association sequencing of 46,544 individuals in the DiscovEHR cohort by Regeneron Genetics Center (Abul-Husn et al.) revealed that a single adenine insertion at the donor splice site of exon 6 (rs72613567:TA, allele frequency ~26% in Europeans and ~33% in East Asians) abolishes HSD17B13 enzymatic activity and confers a 30% to 50% reduction in the risk of metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), alcoholic cirrhosis, and hepatocellular carcinoma (HCC). Crucially, HSD17B13 loss of function does not alter total hepatic triglyceride content (steatosis), but specifically blocks the pathological transition from benign hepatic steatosis to lobular necroinflammation, hepatic stellate cell (HSC) activation, and bridging fibrosis—even in individuals homozygous for the high-risk PNPLA3 I148M (rs738409) steatotic allele.

Rossmann Fold Architecture and Amphipathic N-Terminal Targeting

Human HSD17B13 is a 300-residue homodimeric (or homotetrameric) membrane-associated protein comprising three functional regions:

1. N-Terminal Lipid-Droplet-Targeting Domain (residues 1–35): Contains a hydrophobic membrane-anchoring hairpin (residues 4–22) flanked by basic positively charged residues (Arg23, Lys25, Arg28) and an amphipathic α-helix (residues 71–106) containing a conserved PAT-like motif that inserts directly into the phosphatidylcholine monolayer of hepatic lipid droplets without spanning a bilayer.
2. Core Rossmann-Fold Dinucleotide-Binding Domain (residues 36–185): A classic six-stranded parallel β-sheet sandwiched by α-helices containing the conserved N-terminal TGxxxGxG cofactor-binding motif (Thr43–Gly44–Ala45–Gly46–His47–Gly48–Ile49–Gly50), which preferentially coordinates oxidized NAD⁺ over NADP⁺ (owing to electrostatic repulsion of a 2'-phosphate by Asp69), establishing that HSD17B13 acts predominantly as an oxidative dehydrogenase inside the cytosol ([NAD⁺]/[NADH] ≈ 500–700).
3. Catalytic Active-Site Triad (Ser172–Tyr185–Lys189) and C-Terminal Substrate Loop (residues 186–300): In the canonical SDR mechanism, Tyr185 functions as the general base (its phenolic pK_a lowered to ~6.8 by the adjacent ε-amino group of Lys189 and the 2'-OH of the NAD⁺ nicotinamide ribose), abstracting a proton from the substrate hydroxyl group (17β-OH or retinol C15-OH) while a hydride ion (H⁻) transfers directly to the C4 position of the NAD⁺ nicotinamide ring, stabilized by Ser172.

Retinoid, Eicosanoid, and Pyrimidine-Linked Hepatocyte Signaling

Under physiological conditions, hepatic stellate cells (HSCs in the space of Disse) store ~80% of the body's vitamin A as retinyl esters (retinyl palmitate). During lipotoxic metabolic stress or chronic alcohol exposure, hepatocyte expression of HSD17B13 is upregulated 3- to 6-fold via sterol regulatory element-binding protein 1c (SREBP-1c) and liver X receptor (LXRα). Excess HSD17B13 on hepatocyte lipid droplets oxidizes retinol into reactive retinaldehyde and retinoic acid metabolites, while modifying lipid-droplet phosphatidylcholine remodeling and suppressing the phosphorylation of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL/PNPLA2) co-activation (CGI-58/ABHD5 sequestration). Furthermore, recent structural and metabolomic profiling demonstrates that HSD17B13 promotes pyrimidine degradation (depleting intrahepatic β-aminoisobutyric acid and thymidine) and generates pro-inflammatory lipid mediators (LTB₄ and oxidized phospholipids) that paracrinely activate resident Kupffer cells and trigger TGF-β1/collagen-I (COL1A1) synthesis in neighboring hepatic stellate cells.

Alternative Splicing Defect and Proof of Catalytic Pathogenicity

The protective rs72613567:TA variant insertions an adenine into the 5' splice donor consensus sequence immediately following exon 6 (c.812+2dupA). This single-nucleotide insertion disrupts recognition by the U1 snRNP of the spliceosome, shifting alternative splicing away from full-length wild-type Isoform A (300 amino acids) toward two aberrant transcripts: Isoform B (skipping exon 6 entirely) and Isoform D (retaining a cryptic intronic segment that introduces a premature termination codon, yielding a truncated 274-amino-acid polypeptide missing the C-terminal α-helical substrate-binding lid, residues 263–300). In human liver biopsies from TA/TA homozygotes, Isoform D protein is misfolded, rapidly ubiquitinated via endoplasmic-reticulum-associated degradation (ERAD), and completely devoid of NAD⁺ retinol dehydrogenase activity.

A critical question for drug discovery was whether protection against MASH requires eliminating the physical HSD17B13 protein scaffold from lipid droplets (via siRNA) or whether inhibiting its enzymatic active site with a small molecule is sufficient. The discovery of the rare coding missense variant P260S (rs62305723) answered this question: P260S mutant protein is expressed at wild-type abundance and targets normally to the hepatocyte lipid droplet membrane, yet lacks retinol dehydrogenase activity and confers identical protection against elevated serum alanine aminotransferase (ALT) and histologic steatohepatitis—demonstrating that small-molecule active-site inhibitors (BI-3231, INI-822) can phenocopy genetic loss of function.

Antagonistic Epistasis with PNPLA3 I148M

In human hepatology, the strongest genetic risk factor for fatty liver disease and cirrhosis is the PNPLA3 I148M (rs738409 C>G) variant. Mutant PNPLA3-I148M resists ubiquitin-mediated degradation and accumulates on hepatocyte lipid droplets, where it sequesters the essential lipolytic co-activator CGI-58 (ABHD5) away from ATGL (PNPLA2), blocking triglyceride lipolysis and trapping polyunsaturated fatty acids and retinyl esters. Remarkably, HSD17B13 rs72613567:TA exhibits strong protective epistasis with PNPLA3 I148M: in individuals homozygous for PNPLA3 148M/148M, co-inheritance of the HSD17B13:TA allele blunts the I148M-driven surge in hepatic inflammatory cytokines (IL-6, TNF, CCL2), reduces serum transaminases (ALT/AST), and lowers the odds of progression to advanced bridging fibrosis (F3–F4), cirrhosis, and hepatocellular carcinoma by up to 49% to 58%.

Consistent with the complete absence of adverse clinical phenotypes in humans homozygous for rs72613567:TA (~7% of European and ~11% of East Asian populations are natural human knockouts), comparative mammalian genomics demonstrates that HSD17B13 has undergone recurrent, independent evolutionary inactivation (pseudogenization) across multiple placental orders. Whole-genome alignments and HyPhy RELAX analyses reveal premature stop codons, frameshift indels, and splice-site mutations in HSD17B13 across cetaceans, pinnipeds, frugivorous bats, and subterranean rodents (ω → 0.88–1.00), whereas its ancient housekeeping paralog HSD17B11 (sharing 78% sequence similarity and originating from a tandem duplication on Chr4q22.1) remains under stronger purifying constraint (ω ≈ 0.21). Notably, laboratory mice (Mus musculus) differ from humans in baseline hepatic retinoid handling (Hsd17b13^−/− mice on standard chow showed variable steatotic phenotypes depending on dietary choline/fructose regimes), underscoring why human population genetics (DiscovEHR and UK Biobank) rather than murine knockout screening was essential to uncover the antifibrotic benefit of HSD17B13 inhibition.

How does HSD17B13 loss of function protect the liver against cirrhosis without reducing liver fat (steatosis)?

Unlike ANGPTL3 or PNPLA3 modulators that alter bulk hepatic triglyceride content, HSD17B13 acts downstream of simple triglyceride accumulation (steatosis). On the surface of lipid droplets, wild-type HSD17B13 oxidizes retinol into bioactive retinoids and generates pro-inflammatory lipid mediators (LTB₄ and oxidized phospholipids) while depleting protective pyrimidines. When HSD17B13 is inactivated by the rs72613567:TA variant or GalNAc-siRNA, hepatocyte lipotoxicity, ballooning degeneration, Kupffer cell recruitment, and paracrine activation of collagen-producing hepatic stellate cells are halted even though benign triglyceride droplets remain present.

What is the epistatic relationship between HSD17B13 rs72613567:TA and PNPLA3 I148M?

PNPLA3 I148M (rs738409) is the primary common genetic driver of steatotic liver disease, increasing the risk of MASH cirrhosis ~3- to 5-fold in homozygotes by trapping CGI-58 on lipid droplets. The HSD17B13 rs72613567:TA loss-of-function allele displays direct mitigating epistasis: its protective effect against transaminase elevation (ALT/AST), lobular inflammation, cirrhosis, and hepatocellular carcinoma (HCC) is largest in carriers of the PNPLA3 I148M risk allele, neutralizing nearly half of the excess cirrhosis risk conferred by PNPLA3 I148M.

Why did the discovery of the P260S missense variant enable small-molecule HSD17B13 inhibitor development?

Because the common rs72613567:TA splice variant destroys the HSD17B13 protein, it was initially unclear whether protection against MASH required removing the physical HSD17B13 protein scaffold from lipid droplets (achievable only with siRNA, ASOs, or PROTACs) or merely blocking its enzymatic active site. The rare P260S (rs62305723) missense variant produces a stable, full-length protein that localizes normally to lipid droplets but lacks catalytic retinol dehydrogenase activity—and confers the same clinical liver protection, proving that oral small-molecule active-site inhibitors can treat MASH.

1. Abul-Husn, N. S., Cheng, X., Li, A. H., et al. (2018). "A protein-truncating HSD17B13 variant and protection from chronic liver disease." New England Journal of Medicine, 378(12), 1096–1106. https://doi.org/10.1056/NEJMoa1712191
2. Ma, Y., Belyaeva, O. V., Brown, P. M., et al. (2019). "17-Beta hydroxysteroid dehydrogenase 13 is a hepatic retinol dehydrogenase associated with histological features of nonalcoholic fatty liver disease." Hepatology, 69(4), 1504–1519. https://doi.org/10.1002/hep.30350
3. Thangapandi, V. R., Knittelfelder, O., Brosch, M., et al. (2021). "Loss of hepatic Mboat7 leads to liver fibrosis." Gut, 70(5), 940–950. https://doi.org/10.1136/gutjnl-2020-320853
4. Luukkonen, P. K., Sakuma, I., Gaspar, R. C., et al. (2023). "Inhibition of HSD17B13 protects against liver fibrosis by modulating pyrimidine catabolism in humans and mice." Gastroenterology, 165(5), 1222–1237. https://doi.org/10.1053/j.gastro.2023.07.013