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Glucagon and thyroid hormone (T) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.

SummaryConcomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.

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Conflicts of Interest Statement D.L. reports funding by a postdoctoral fellowship from the Society for Immunotherapy of Cancers which is funded in part by an educational grant from Bristol-Meyers Squibb (BMS). BMS has had no input into the conception, conduct, or reporting of the submitted work. D.C. has received consulting (GSK, Lilly, Boston Pharmaceuticals) and travel/speaking (Merck) support, outside the scope of the present work. G.M.B. had sponsored research agreements with Takeda Oncology, Palleon Pharmaceuticals, Olink Proteomics, which were not used to support this work. She served as a speaker for Novartis and on scientific advisory boards for Nektar Therapeutics and Novartis and consults for Merck, all of which are outside the scope of this work. P.K.B has consulted