Abstract:
Nonalcoholic fatty liver disease (NAFLD) is a slowly developing disease that includes a wide range of pathological conditions. In the first stage, NAFLD is characterized by simple hepatic steatosis (NAFL, nonalcoholic fatty liver) that might progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular carcinoma. It is known that obesity, type 2 diabetes mellitus, and dyslipidemia are the most common metabolic risk factors associated with both the development and progression of NAFLD. Scientists and physicians estimate that nowadays between 20% to 30% of general population in the western world suffer from NAFLD. Globally it makes more than a billion people worldwide. Besides fat accumulation in hepatocytes, a chronic local inflammation of low intensity is a characteristic feature of NAFLD. Therefore, proteins involved in inhibition of inflammatory response have a very significant impact on this disease.
One of the important protein involved in a negative regulation of inflammation is a Monocyte Chemoattractant Protein-Induced Protein 1 (MCPIP1). MCPIP is a member of CCCH-zinc finger protein family, consisting of four proteins (MCPIP1-4) encoded by four genes (Zc3h12a-d in mouse and ZC3H12A-D in humans). Thanks to detailed sequence alignment combined with in vitro experiments, a putative PIN domain responsible for MCPIP1 RNase activity was described for the first time in 2009. After years of study we know, that MCPIP1 binds to mRNAs’ 3’UTR fragments and digests a stem-loop structures. Such endoribonuclease activity of MCPIP1 shortens a half-life of selected transcripts and reduces amount of proteins What is more, MCPIP1 is responsible for degradation of translationally active transcripts and is important particularly in the initial stage of inflammation. The anti-inflammatory properties of MCPIP1 have also been confirmed in vivo. Mice deficient in this protein, spontaneously develop systemic inflammatory response leading to splenomegaly, lymphadenopathy, hyperimmunoglobulinemia and ultimately to death within 12 weeks. Moreover, macrophages and lymphocytes isolated from spleen of Zc3h12a knock-out animals (MCPIP1 protein is not expressed) showed increased expression of inflammatory genes, and enhanced activity of JNK and IkappaB.
So far, MCPIP1 was shown to modulate a wide plethora of cellular processes e.g. differentiation, proliferation, migration or apoptosis, which are all important for obesity and NAFLD development and progression.
Audience Take Away:
- Description of MCPIP RNase family (mechanism of action, function in tissue homeostasis).
- New results concerning MCPIP1 role in adipogenesis, obesity and NAFLD.
