HSD17B13 is a liver lipid droplet-associated enzyme that interacts with steroid substrates, bioactive lipids, and retinol. Three unique HSD17B13 genetic variants have been discovered that offer protection against harm in NASH, alcoholic liver disease, and hepatocellular carcinoma. 

The exons 1-7 of mouse Hsd17b13 gene that encode the whole molecule were replaced by human counterparts in B-hHSD17B13 mice plus. The promoter, 5’UTR and 3’UTR region of the mouse gene are replaced by human counterparts. 

Human HSD17B13 mRNA was detectable only in homozygous B-hHSD17B13 mice plus, but not in wild-type C57BL/6 mice. 

HSD17B13 was detectable in liver of homozygous B-hHSD17B13 mice plus. 

Human HSD17B13 targeted nucleic acid drugs (synthesized according to patents) were efficacious in B-hHSD17B13 mice plus.

Gene targeting strategy for B-hHSD17B13 mice plus. The exons 1-7 of mouse Hsd17b13 gene that encode the whole molecule were replaced by human counterparts in B-hHSD17B13 mice plus. The promoter, 5’UTR and 3’UTR region of the mouse gene are replaced by human counterparts.

Species specific analysis of HSD17B13 gene expression in wild-type C57BL/6 mice and homozygous humanized B-hHSD17B13 mice plus by RT-PCR. Livers were collected from wild-type C57BL/6 mice (+/+) and homozygous B-hHSD17B13 mice plus (H/H). Mouse Hsd17b13 mRNA was detectable only in wild-type C57BL/6 mice. Human HSD17B13 mRNA was detectable only in homozygous B-hHSD17B13 mice plus, but not in wild-type C57BL/6 mice.

Strain specific HSD17B13 expression analysis in wild-type C57BL/6 mice and homozygous humanized B-hHSD17B13 mice plus by Western. Various tissue lysates were collected from wild-type C57BL/6 mice (+/+)  and homozygous B-hHSD17B13 mice plus (H/H), and then analyzed by western blot with anti-HSD17B13 antibody (abcam, ab316153). 40 μg total proteins were loaded for western blotting analysis. Human HSD17B13 was only detected in liver.

The inhibitory efficiency of the nucleic acid drugs against human HSD17B13 mRNA in liver tissue in homozygous B-hHSD17B13 mice plus. B-hHSD17B13 mice plus were randomly divided into five groups (10 weeks old). The human HSD17B13 targeted nucleic acid drugs (synthesized according to patents) and PBS were administered to the mice individually. The nucleic acid drugs were administered in the form of PBS aqueous solution. The mice were sacrificed on day 7, and the liver tissue was collected to detect the expression level of human HSD17B13 mRNA by qPCR. (A) The schematic diagram of experimental processing. (B) The expression of human HSD17B13 mRNA in liver after treatment. The human HSD17B13 in the treatment group was reduced compared to the control group, demonstrating that B-hHSD17B13 mice plus provide a powerful preclinical model for in vivo evaluation of human HSD17B13 targeted nucleic acid drugs. Values are expressed as mean ± SEM.