Grant: Project Grant

The liver controls several functions including lipid and glucose metabolism, cholesterol and bile acid (BA) synthesis, lipoprotein secretion and ketone bodies production. Most of the metabolic functions fulfilled by the liver are carried out by the hepatocytes, which constitute the main cell type of this organ. Nutrient excess and obesity are well known to impact the function of hepatocytes. Numerous studies have linked hepatocyte dysfunction to the development of several pathological conditions including fatty liver disease, dyslipidemia, type 2 diabetes, and cardiovascular diseases. Despite progresses, the precise molecular mechanisms by which nutritional signals control liver-specific processes to regulate systemic metabolism remain incompletely characterized. In recent work, we identified Hydroxysteroid dehydrogenase-like 2 (HSDL2) as a poorly characterized protein expressed in catabolic hepatocytes. HSDL2 is a member of the short-chain dehydrogenases/reductases family that is highly conserved in evolution. We found that HSDL2 localizes to the mitochondria and its expression is induced by fasting and insulin resistance. Supporting a role for HSDL2 in regulating cellular metabolism, we found that HSDL2 depletion decreased cholesterol conversion to BAs. In mice, liver-specific depletion of HSDL2 altered BA pool composition and reduced postprandial cholesterol levels. In details, we showed that HSDL2 loss decreased the production of 12a-hydroxylated (12a-OH) BAs, a group of BAs whose production is linked to both dyslipidemia and insulin resistance in mice and humans. These results position HSDL2 as a novel regulator of catabolism that impacts metabolism in response to nutritional cues. Here, we propose an innovative research project combining the use of various in vitro approaches, animal models, and human clinical samples, to expand the understanding of how HSDL2 impacts normal physiology and the development of metabolic diseases.