Project description:mRNA expression was compared between wild type and hepatocyte-specific caveolin-1 knockout livers in healthy and non-alcoholic fatty liver disease (NAFLD) mice mRNA expression was compared between gender
Project description:The ER-resident prote in fat-inducing transcript 2 (FIT2) catalyzes acyl-CoA cleavage in vitro, and in cells is required for endoplasmic reticulum (ER)homeostasis and normal lipid storage. The gene encoding FIT2 is essential for viability of mice and worms. Whether FIT2 acts as anacyl-CoA diphosphatase in vivo and how this activity affects liver, where the protein was discovered,is unknown. Here, we report that hepatocyte-specific Fitm2 knockout (FIT2-LKO) mice exhibited elevated acyl-CoA levels, ER stress, and signs of liver injury. FIT2-LKO mice had increased triglyceride (TG) content in liver when fed a chow diet, compared with control littermates due in part to impaired secretion of TG-rich lipoproteins and reduced capacity for fatty acid oxidation. Challenging FIT2-LKO mice with a high-fat diet to increase FIT2 acyl-CoA substrates worsened hepatic ER stress and liver injury, yet unexpectedly reversed the steatosis phenotype, similar to what is observed in FIT2-deficient cells loaded with fatty acids. Our findings show that FIT2 acts as anacyl-CoA diphosphatase in vivo and is crucial for normal hepatocyte function and ER homeostasis in murine liver
Project description:Unperturbed cholesterol homeostasis is important for normal development and sexual maturation in mice. Cyp51 is the rate limiting step in the post-lanosteorl part of cholesterol biosynthesis. Unlike the full body knockout, hepatocyte specific Cyp51 knockout mice survive throughout adulthood, however their livers are severly affected. Several of the hepatocyte specific Cyp51 knockout mice develop severe liver injury or die prior to reaching adulthood (from 4-10 weeks of age; designated as runts). We aim to uncover the timing and the mechanistic background governing the liver damage and sex differences. Hepatocyte-specific Cyp51 knockout and wild type mice on a mixed background (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated at the pre pubertal (3 weeks), late pubertal (6 weeks) and adult (19 weeks) stage of development. This age span allows us to also observe the impact of sexual maturation on the disease development, as the liver is one of the most sexually dimorphic non-reproductive organs. Runt mice were evaluated to differentiate them from the other KO mice with milder conditions.
