Inhibition of the Low Molecular Weight Protein Tyrosine Phosphatase (LMPTP) as a Potential Therapeutic Strategy for Hepatic Progenitor Cells Lipotoxicity-Short Communication.

Michalina Alicka,Michael Roecken,Katarzyna Kornicka-Garbowska,Krzysztof Marycz

doi:10.3390/ijms20235873

Abstract

Equine metabolic syndrome (EMS) is a cluster of metabolic disorders, such as obesity, hyperinsulinemia, and hyperleptinemia, as well as insulin resistance (IR). In accordance with the theory linking obesity and IR, excessive accumulation of lipids in insulin-sensitive tissues (lipotoxicity), like liver, alters several cellular functions, including insulin signaling. Therefore, the purpose of the study was to isolate equine hepatic progenitor-like cells (HPCs) and assess whether inhibition of low molecular weight protein tyrosine phosphatase (LMPTP) affects the expression of genes involved in macroautophagy, chaperone-mediated autophagy (CMA), endoplasmic reticulum stress, and mitochondrial dynamics in a palmitate-induced IR model. We demonstrated that LMPTP inhibition significantly enhanced expression of heat shock cognate 70 kDa protein (HSC70), lysosome-associated membrane protein 2 (LAMP2), and parkin (PRKN), all master regulators of selective autophagy. We also observed downregulation of C/EBP homologous protein (CHOP), activating transcription factor 6 (ATF6) and binding immunoglobulin protein encoded by the HSPA gene. Moreover, LMPTP inhibition increased alternative splicing of X-box binding protein 1 (XBP1), suggesting high endonuclease activity of inositol-requiring enzyme 1 alpha (IRE1α). Taken together, our data provide convincing evidence that LMPTP inhibition reverses palmitate-induced insulin resistance and lipotoxicity. In conclusion, this study highlights the role of LMPTP in the regulation of CMA, mitophagy, and ER stress, and provides a new in vitro model for studying HPC lipotoxicity in pre-clinical research.

Highlights

Equine metabolic syndrome (EMS) is a set of characteristic symptoms, including insulin resistance (IR), hyperinsulinemia, hyperleptinemia, increased generalized and regional adiposity, as well as local and systemic inflammation [1]
Hepatic progenitor cells (HPCs) are bipotential cells residing in normal liver tissue
The results suggest that cultured hepatic progenitor-like cells (HPCs) expressed markers characteristic for hepatic stem cells, whereas they did not express as α-fetoprotein (AFP), platelet and endothelial cell adhesion molecule 1 (PECAM1), CD90, and CD105 (ASCs markers)

Summary

Introduction

Equine metabolic syndrome (EMS) is a set of characteristic symptoms, including insulin resistance (IR), hyperinsulinemia, hyperleptinemia, increased generalized and regional adiposity, as well as local and systemic inflammation [1]. Those metabolic disorders are highly associated with the occurrence of laminitis—an extremely painful and life-threating disease, which can lead to an animal’s euthanasia. There is evidence that in horses, excessive intake of fodder rich in non-structural carbohydrates (NSCs) increases the activity of hepatic de novo lipogenesis, leading to lipotoxicity, and IR [2]. Excessive accumulation of toxic triglyceride in the liver cells contributes to the development of non-alcoholic fatty liver disease (NAFLD) [3]. IR occurs primarily in insulin-sensitive tissues, like liver, adipose tissue, and muscle, and may be caused by several mechanisms, e.g., endoplasmic reticulum (ER) stress, impaired mitochondrial dynamics, and autophagy [4,5,6,7]

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