The lethal form of Cushing's in 7B2 null mice is caused by multiple metabolic and hormonal abnormalities.
The neuroendocrine-specific protein 7B2, which serves as a molecular escort for proPC2 in the secretory pathway, promotes the production of enzymatically active PC2 and may have non-PC2 related endocrine roles. Mice null for 7B2 exhibit a lethal phenotype with a complex Cushing's-like pathology, which develops from intermediate lobe ACTH hypersecretion as a consequences of interruption of PC2-mediated peptide processing as well as undefined consequences of the loss of 7B2. In this study we investigated the endocrine and metabolic alterations of 7B2 null mice from pathological and biochemical points of view. Our results show that 7B2 nulls exhibit a multisystem disorder that includes severe pathoanatomical and histopathologic alterations of vital organs, including the heart and spleen but most notably the liver, in which massive steatosis and necrosis are observed. Metabolic derangements in glucose metabolism result in glycogen and fat deposition in liver under conditions of chronic hypoglycemia. Liver failure is also likely to contribute to abnormalities in blood coagulation and blood chemistry, such as lactic acidosis. A hypoglycemic crisis coupled with respiratory distress and intensive internal thrombosis most likely results in rapid deterioration and death of the 7B2 null.
Sarac
Miroslav S
MS
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Zieske
Arthur W
AW
Lindberg
Iris
I
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002423:Cause of Death; D003345:Corticosterone / Q000097:blood; D003480:Cushing Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006728:Hormones / Q000235:genetics / Q000378:metabolism*; D007035:Hypothermia / Q000209:etiology / Q000235:genetics; D019344:Lactic Acid / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008274:Magnesium / Q000097:blood / Q000378:metabolism; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000235:genetics / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D051859:Neuroendocrine Secretory Protein 7B2; D010907:Pituitary Hormones / Q000235:genetics* / Q000502:physiology; D011863:Radioimmunoassay; D012640:Seizures / Q000209:etiology / Q000235:genetics; D014018:Tissue Distribution
D001786:Blood Glucose; D006728:Hormones; D009419:Nerve Tissue Proteins; D051859:Neuroendocrine Secretory Protein 7B2; D010907:Pituitary Hormones; D019344:Lactic Acid; D000324:Adrenocorticotropic Hormone; D006003:Glycogen; D005934:Glucagon; D008274:Magnesium; D005947:Glucose; D003345:Corticosterone; D008797:Metyrapone