MAPK Phosphatase-3 Mediates Chronic Endoplasmic Reticulum Stress Promoting Hepatic Gluconeogenesis

Long-term nutritional excess causes hepatic steatosis, endoplasmic reticulum (ER) stress, hyperglycemia, and hyperlipidemia. Mitogen-activated protein kinase phosphatase-3 (MKP-3) is a well-established stress-regulated protein and a regulator of gluconeogenesis. Our previous study revealed that acute ER stress reduced gluconeogenesis and MKP-3 protein stability. However, the expression of MKP-3 and its regulatory mechanisms in chronic ER stress remain unclear. The aim of this study was to investigate the effects of chronic ER stress on hepatic MKP-3 expression and its role in the regulation of gluconeogenesis. The results show that long-term administration of thapsigargin (Tg) or palmitic acid promoted gene expression of <i>Mkp-3</i> and gluconeogenic genes <i>Pepck</i>, <i>G6pc</i>, and <i>Pgc1α</i> in primary mouse hepatocytes. In addition, a long-term high-fat diet (HFD) or Tg administration significantly increased hepatic ER stress and blood glucose level in mice, while inducing the expression of <i>Mkp-3</i> and hepatic gluconeogenic genes <i>Pepck</i>, <i>G6pc</i> and <i>Pgc1α</i>. Further study revealed that liver-specific <i>Mkp-3</i> knockout (<i>Mkp-3</i> LKO) reversed the blood glucose level and expression levels of gluconeogenic genes those were induced by long-term HFD in mice. Moreover, activation of the PKR-like ER kinase (PERK) by its agonist increased hepatic <i>Mkp-3</i> expression, whereas inhibitor of PERK suppressed the expression of <i>Mkp-3</i> under Tg administration. These results suggest that chronic high-fat diet might promote hepatic gluconeogenesis via the PERK/MKP-3 pathway. Consequently, this study identified a potential therapeutic target for treating obesity-related hyperglycemia.