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

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.

Sex Hormone Binding Globulin (SHBG) Mitigates ER Stress in Hepatocytes In Vitro and Ex Vivo

“…Recently, increasing attention has been paid to understanding the role of liver deterioration during IR, metabolic dysfunction, and lipotoxicicty, as these represent a crucial component of MetS and MS [ 9 , 10 ]. Progressive IR in peripheral tissues leads to increased accumulation of free fatty acids (FFA) in the liver, and in turn enhances triglyceride and very low-density lipoprotein (VLDL) synthesis in hepatocytes.…”

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

“…Mitochondria are highly dynamic organelles that constantly undergo fusion and fission, which are critical for mitochondrial homeostasis, mtDNA inheritance and intracellular distribution of the mitochondria [14][15][16][17]. Tight regulation of mitochondrial fission and fusion is required to constantly adapt to altering physiological needs [18][19][20]. When individual mitochondria or their constituents such as OXPHOS protein complexes and lipids are irreversibly damaged, they are degraded through mitophagy, a lysosome-dependent proteolytic system in order to maintain cellular homeostasis [21][22][23][24].…”

Inhibition of Protein-Tyrosine Phosphatase PTP1B and LMPTP Promotes Palmitate/Oleate-Challenged HepG2 Cell Survival by Reducing Lipoapoptosis, Improving Mitochondrial Dynamics and Mitigating Oxidative and Endoplasmic Reticulum Stress

“…These observations highlight the fact that PTP1B acts as an upstream regulator of Sirt1 and that its inhibition provides a valuable strategy for the restoration and maintenance of mitochondrial homeostasis [65,66]. For its part, LMPTP inhibition has been previously demonstrated to promote mRNA levels of Fis1 and Prkn transcripts, without affecting expression rate of Mfn1 and Pink1 in a model of HPCs challenged with palmitate, highlighting a potential regulatory role of LMPTP on mitochondrial homeostasis [59]. Oxidative stress clearly plays a critical role in the development of liver fibrosis.…”

“…Obtained results demonstrated also that LMPTP inhibition using its selective modulator (Compound 23), can successfully prevent and reduce lipids-induced apoptosis in liver. Similarly, Alicka et al [59], reported on the beneficial effect of LMPTP inhibition on equine hepatic progenitor-like cells (HPCs) survival in the course of PA-induced lipoapoptosis, evidenced by the observed changes in calcein-acetoxymethyl (AM) / propidium iodine (PI) fluorescence intensity. Taken together, these data indicate that LMPTP is also implicated in regulating cell survival during cellular metabolic disruption.…”