Recombinant CTRP3 as Protein Therapeutics for Non-alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD), a major cause of liver dysfunction, is characterized by intrahepatic triacylglycerol (TAG) overaccumulation resulting from excess dietary lipids and de novo fatty acid synthesis. NAFLD is closely linked to insulin resistance and uncontrolled gluconeogenesis and, hence, is often associated with obesity. Yet, while NAFLD is a reversible condition, to date, therapeutic options are limited. Hence, this invention describes a novel role of C1q/TNF-related protein (CTRP)-3 in the direct regulation of liver lipid metabolism, unraveling CTRP3 as a valuable new protein therapeutic for the treatment and prevention of fatty liver diseases. Advantages include:

• Allows administration of a physiological protein without adverse health effects
• Efficient therapy of different types of fatty liver diseases and associated diet-induced obesity

Johns Hopkins researchers have identified a formerly unrecognized activity of CTRP3 in directly regulating lipid metabolism in liver, useful as a novel protein therapeutic for fatty liver diseases. CTRPs are widely expressed secreted metabolic regulators of insulin sensitivity and energy balance. Interestingly, whilst CTRP3 had previously been attributed different functions in hepatic gluconeogenesis and protection of myocardic infections, this invention discovered a yet unknown direct protective role of CTRP3 in attenuating diet-induced fatty liver. Transgenic mice overexpressing CTRP3 fed a high-fat diet show downregulation of gluconeogenesis, leading to significantly greater insulin sensitivity. Further, serum cholesterol levels and the expression of TAG biosynthetic enzymes are substantially lowered, altogether conferring a striking resistance of transgenic mice to the development of fatty liver disease. Importantly, the short-term daily administration of recombinant CTRP3 in vitro similarly modulates liver lipid metabolism. Therefore, this technology provides protein and nucleic acid sequences of CTRP3 or functional variants thereof, useful as novel therapeutics for the prevention and treatment of different types of fatty liver diseases, such as NAFLD.

Patent Status: Granted US Patent 9,623,080

Associated Publications: Am J Physiol Gastrointest Liver Physiol. 2013 Aug 1;305(3):G214-24.
 

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