Unmet NeedObesity is a leading preventable cause of death worldwide, and it is associated with a number of comorbidities, including Non-alcoholic Fatty Liver Disease (NAFLD). Fatty liver is the accumulation of triglycerides and other fats in the liver cells. The amount of fatty acid in the liver depends on the balance between the processes of delivery and removal. In some patients, fatty liver may be accompanied by hepatic inflammation and liver cell death (steatohepatitis). Potential pathophysiologic mechanisms for fatty liver include the following: decreased mitochondrial fatty acid beta-oxidation, increased endogenous fatty acid synthesis or enhanced delivery of fatty acids to the liver, and deficient incorporation or export of triglycerides as very low-density lipoprotein (VLDL). However, there are no effective therapeutics to treat this disorder.
Technology OverviewJohns Hopkins researchers have identified C1q/TNF-related protein 1 (CTRP1), a regulator of metabolism homeostasis, as a potential target and therapy to treat fatty liver disease. CTRP1 is highly expressed in adipose tissue and its circulating levels are modulated by the metabolic and inflammatory states of animals. Consistent with a metabolic role, administration of recombinant CTRP1 to wild-type mice acutely lowers blood glucose, and chronic overexpression of CTRP1 in transgenic mice enhances AMP-activated protein kinase (AMPK) activation and skeletal muscle fat oxidation, while attenuating insulin resistance induced by high-fat feeding. Its expression is upregulated by the anti-diabetic drug, rosiglitazone, as well as in animals lacking the insulin-sensitizing hormone, adiponectin. The developed method provides for modulating CTRP1 levels or providing CTRP1 as a biologic therapy, in order to treat fatty liver disease.
Stage of DevelopmentPreclinical data using a Ctrp1 knockout (KO) mice fed a low-fat diet (LFD) demonstrated that these animals developed insulin resistance and hepatic steatosis. Impaired glucose metabolism in Ctrp1-KO mice was associated with increased hepatic gluconeogenic gene expression and decreased skeletal muscle glucose transporter GLUT4 levels and AMPK activation. Loss of CTRP1 enhanced clearance of orally-administered lipids but did not affect hepatic VLDL-triglyceride export; this in part contributed to higher hepatic triglyceride levels in Ctrp1-KO animals. In contrast to triglycerides, hepatic cholesterol levels were reduced in Ctrp1-KO mice, paralleling the reduced expression of cholesterol synthesis genes. Contrary to expectations, when challenged with a high-fat diet (HFD) to induce obesity, Ctrp1-KO mice had increased physical activity and reduced body weight, adiposity, and expression of lipid synthesis and fibrotic genes in adipose tissue. Due in part to increased hepatic AMPK activation and reduced expression of lipid synthesis genes, Ctrp1-KO mice fed a HFD also had reduced liver and serum triglyceride and cholesterol levels.
PublicationsAm J Physiol Endocrinol Metab. 2016 Oct 1;311(4):E678-E697
