👤 L Mairinoja

The function of hydroxysteroid dehydrogenase 12 (HSD17B12) in lipid metabolism is poorly understood. To study this further, we created mice with hepatocyte-specific knockout of HSD17B12 (LiB12cKO). From 2 months on, these mice showed significant fat accumulation in their liver. As they aged, they also had a reduced whole-body fat percentage. Interestingly, the liver fat accumulation did not result in the typical formation of large lipid droplets (LD); instead, small droplets were more prevalent. Thus, LiB12KO liver did not show increased macrovesicular steatosis with the increasing fat content, while microvesicular steatosis was the predominant feature in the liver. This indicates a failure in the LD expansion. This was associated with liver damage, presumably due to lipotoxicity. Notably, the lipidomics data did not support an essential role of HSD17B12 in fatty acid (FA) elongation. However, we did observe a decrease in the quantity of specific lipid species that contain FAs with carbon chain lengths of 18 and 20 atoms, including oleic acid. Of these, phosphatidylcholine and phosphatidylethanolamine have been shown to play a key role in LD formation, and a limited amount of these lipids could be part of the mechanism leading to the dysfunction in LD expansion. The increase in the Cidec expression further supported the deficiency in LD expansion in the LiB12cKO liver. This protein is crucial for the fusion and growth of LDs, along with the downregulation of several members of the major urinary protein family of proteins, which have recently been shown to be altered during endoplasmic reticulum stress. Show less

Hydroxysteroid 17β dehydrogenase 12 (HSD17B12) is suggested to be involved in the elongation of very long chain fatty acids. Previously, we have shown a pivotal role for the enzyme during mouse development. In the present study we generated a conditional Show less

Hydroxysteroid (17β) dehydrogenase type 3 (HSD17B3) deficiency causes a disorder of sex development in humans, where affected males are born with female-appearing external genitalia, but are virilized during puberty. The hormonal disturbances observed in the Hsd17b3 knockout mice (HSD17B3KO), generated in the present study, mimic those found in patients with HSD17B3 mutations. Identical to affected humans, serum T in the adult HSD17B3KO mice was within the normal range, while a striking increase was detected in serum A-dione concentration. This resulted in a marked reduction of the serum T/A-dione ratio, a diagnostic hallmark for the patients with HSD17B3 deficiency. However, unlike humans, male HSD17B3KO mice were born with normally virilized phenotype, but presenting with delayed puberty. In contrast to the current belief, data from HSD17B3KO mice show that the circulating T largely originates from the testes, indicating a strong compensatory mechanism in the absence of HSD17B3. The lack of testicular malignancies in HSD17B3KO mice supports the view that testis tumors in human patients are due to associated cryptorchidism. The HSD17B3KO mice presented also with impaired Leydig cell maturation and signs of undermasculinization in adulthood. The identical hormonal disturbances between HSD17B3 deficient knockout mice and human patients make the current mouse model valuable for understanding the mechanism of the patient phenotypes, as well as endocrinopathies and compensatory steroidogenic mechanisms in HSD17B3 deficiency. Show less