Receptor-interacting protein 140 (RIP140) is best known for its functional role as a wide-spectrum transcriptional
co-regulator. It is highly expressed in metabolic tissues including mature adipocyte. In the past decade, molecular
biological and biochemical studies revealed extensive and sequential post-translational modifications (PTMs) of RIP140.
Some of these PTMs affect RIP140’s sub-cellular distribution and biological activities that contribute to the development
and progression of metabolic diseases. The biological activity of RIP140 that translocates to the cytoplasm in adipocytes
is to regulate glucose uptake, adiponectin secretion and lipolysis. Accumulation of RIP140 in the cytoplasm promotes
adipocyte dysfunctions, and provides a biomarker of early stages of metabolic diseases. Administering compounds that
reduce cytoplasmic accumulation of RIP140 in high fat diet-fed animals can ameliorate metabolic dysfunctions, manifested
in improving insulin sensitivity and adiponectin secretion, and reducing incidences of hepatic steatosis. This review
summarizes studies demonstrating RIP140’s PTMs and biological activities in the cytoplasm of adipocyte, signaling
pathways stimulating these PTMs, and a proof-of-concept that targeting cytoplasmic RIP140 can be an effective strategy
in managing metabolic diseases.
Keywords: RIP140, Post translational modification (PTM), Adipocyte, Type II diabetes mellitus (T2DM), Endothelin-1 (ET-
1), Ambresentan, GLUT4, Adiponectin, Nuclear translocation, Biomarker, Therapeutics.
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