Hydroxysteroid (17β) dehydrogenase 12 is essential for metabolic homeostasis in adult mice

Abstract

Hydroxysteroid 17-beta 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 Hsd17b12 knockout (HSD17B12cKO) mouse model by breeding mice homozygous for a floxed Hsd17b12 allele with mice expressing the tamoxifen-inducible Cre recombinase at the ROSA26 locus. Gene inactivation was induced by administering tamoxifen to adult mice. The gene inactivation led to a 20% loss of body weight within six days, associated with drastic reduction in both white (83% males, 75% females) and brown (65% males, 60% females) fat, likely due to markedly reduced food and water intake. Furthermore, the knockout mice showed sickness behavior and signs of liver toxicity, specifically microvesicular hepatic steatosis and increased serum alanine aminotransferase (4.6-fold in males, 7.7-fold in females). The hepatic changes were more pronounced in females than males. Pro-inflammatory cytokines, such as interleukin 6 (IL-6), IL-17 and granulocyte-colony stimulating factor were increased in the HSD17B12cKO mice indicating inflammatory response. Serum lipidomics study showed an increase in the amount of dihydroceramides, despite the dramatic overall loss of lipids. In line with the proposed role for HSD17B12 in the fatty acid elongation, we observed accumulation of ceramides, dihydroceramides, hexosylceramides and lactosylceramides with shorter than 18-carbon fatty acid side chains in the serum. The results indicate that HSD17B12 is essential for proper lipid homeostasis, and HSD17B12 deficiency rapidly results in fatal systemic inflammation and lipolysis in adult mice.

A set of gene knockouts as a resource for global lipidomic changes

“…Its gene, termed HSD17B12, was also knocked out in our screen. Lipidomics analysis of blood serum of a mouse KO showed accumulation of several sphingolipid classes with shorter than 18-carbon fatty acid side chains, in line with the proposed role for HSD17B12 in fatty acid elongation 62 . HSD17B12 has been reported to have specificity for C-18, C-20, and C-22 carbon atoms length 63 , 64 .…”

Lipid homeostasis is essential for a maximal ER stress response

“…This would allow us to saturate cellular exposure to lipid intermediates and avoid the possibility of bacteria processing the intermediates prior to digestion by C. elegans animals. Similar to let-767 in C. elegans , the 3-ketoacyl reductase in mice, HSD17B12, was found to be essential for development in mice and knockout of the gene in adult mice resulted in reduced body weight, reduced lipid content, and caused liver toxicity hypothesized to be from accumulation of toxic intermediates [46], [47]. 3-ketoacyl reductases perform the second step in fatty acid synthesis/elongation, metabolizing 3-oxoacyl-CoA to 3-hydroxyacyl-CoA (Fig.5A) [48].…”

Identifying Environmental Endocrine Disruptors Associated With the Age at Menarche by Integrating a Transcriptome-Wide Association Study With Chemical-Gene-Interaction Analysis

“…Under extreme circumstances, haploinsufficiency of the HSD17B12 gene in female mice resulted in subfertility. HSD17B12 can affect fatty acid elongation and ceramide accumulation in the serum ( 38 ). Previous data showed that central ceramides participate in the timing of female puberty ( 39 ), suggesting that HSD17B12 could be a candidate gene for female puberty.…”