ABSTRACT
Background: Glycogen storage disease type Ia (GSD Ia), also known as von Gierke disease, is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, the enzyme that catalyzes the final step of gluconeogenesis and glycogenolysis. The accumulation of glucose-6-phosphate leads to increased glycogen and triglyceride levels in the liver. Patients with GSD Ia can develop steatohepatitis, cirrhosis, and increased risk for hepatocellular adenomas and carcinomas. We previously showed that animal models of GSD Ia had defective autophagy and dysfunctional mitochondria. In this study, we examined the effect of VK2809, a liver-specific thyroid hormone receptor ß agonist, on hepatic steatosis, autophagy, and mitochondrial biogenesis in a mouse model of GSD Ia. Methods:G6pc-/--deficient (GSD Ia) mice were treated with VK2809 or vehicle control by daily intraperitoneal injection for four days. The hepatic triglyceride and glycogen were determined by biochemical assays. Autophagy and mitochondrial biogenesis were measured by Western blotting for key autophagy and mitochondrial markers. Results: VK2809 treatment decreased hepatic mass and triglyceride content in GSD Ia mice. VK2809 stimulated hepatic autophagic flux as evidenced by increased microtubule-associated protein light chain 3-II (LC3B-II), decreased p62 protein levels, activation of AMP-activated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) signaling, enhancement of protein levels of ATG5-ATG12, and increased lysosomal protein expression. VK2809 also increased the expression of carnitine palmitoyltransferase 1a (CPT1α) and fibroblast growth factor 21 (FGF21), as well as mitochondrial biogenesis to promote mitochondrial ß-oxidation. Conclusions: In summary, VK2809 treatment decreased hepatic triglyceride levels in GSD Ia mice through its simultaneous restoration of autophagy, mitochondrial biogenesis, and ß-oxidation of fatty acids. Liver-specific thyromimetics represent a potential therapy for hepatosteatosis in GSD Ia as well as nonalcoholic fatty liver disease.
Subject(s)
Autophagy/drug effects , Fatty Liver/metabolism , Glycogen Storage Disease Type I/metabolism , Liver/drug effects , Mitochondria, Liver/drug effects , Organophosphonates/pharmacology , Thyroid Hormone Receptors beta/agonists , Animals , Disease Models, Animal , Fatty Acids/metabolism , Glucose-6-Phosphatase/genetics , Glycogen/metabolism , Glycogen Storage Disease Type I/genetics , Liver/metabolism , Mice , Mice, Knockout , Mitochondria, Liver/metabolism , Organelle Biogenesis , Oxidation-Reduction , Triglycerides/metabolismABSTRACT
A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays.
Subject(s)
Amides/chemistry , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Piperidines/chemistry , Amides/pharmacology , Amides/therapeutic use , Animals , Bone Resorption/drug therapy , Bone Resorption/enzymology , Cathepsin K , Cathepsins/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Cysteine Proteinase Inhibitors/therapeutic use , Humans , Mice , Piperidines/pharmacology , Piperidines/therapeutic useABSTRACT
A highly functionalized perhydroindole is formed by the intramolecular [π4s+π2s] cycloaddition of a 2-azaallyl anion with a vinyl sulfide [Eq. (a)]. This is the key step in the total synthesis of (+)-coccinine, the enantiomer of the Amaryllidaceae alkaloid (-)-coccinine.
