No abstract

Targeted protein degradation through ubiquitination is an important step in the regulation of glucose metabolism. Here, we present evidence that the DDB1-CUL4A ubiquitin E3 ligase functions as a novel metabolic regulator that promotes FOXO1-driven hepatic gluconeogenesis. In vivo, hepatocyte-specific Ddb1 deletion leads to impaired hepatic gluconeogenesis in the mouse liver but protects mice from high-fat diet–induced hyperglycemia. Lack of Ddb1 downregulates FOXO1 protein expression and impairs FOXO1-driven gluconeogenic response. Mechanistically, we discovered that DDB1 enhances FOXO1 protein stability via degrading the circadian protein cryptochrome 1 (CRY1), a known target of DDB1 E3 ligase. In the Cry1 depletion condition, insulin fails to reduce the nuclear FOXO1 abundance and suppress gluconeogenic gene expression. Chronic depletion of Cry1 in the mouse liver not only increases FOXO1 protein but also enhances hepatic gluconeogenesis. Thus, we have identified the DDB1-mediated CRY1 degradation as an important target of insulin action on glucose homeostasis.

No abstract

Plasma cell disorders, such as multiple myeloma, can cause numerous derangements of hemostasis. In this case report, we present a life-threatening coagulopathy in a patient with progressing multiple myeloma in which the antibody-producing heparin-like activity is a free light chain. The patient's bleeding was successfully treated using protamine sulfate, which then allowed treatment of her plasma cell leukemia. In the literature, other authors have reported similar patients who have responded to protamine sulphate either in vitro or in vivo, providing further evidence for the role of protamine sulfate in the reversal of coagulopathy and resolution of bleeding diathesis. Standard treatments of transfusion with fresh frozen plasma and cryoprecipitate are likely to be ineffective in life-threatening bleeding related to this mechanism (heparin-like effect), and it is essential that treating physicians are aware of this potential mechanism of bleeding in their patients.