Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

Abstract

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH 2 -terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis. O besity is a major problem globally, and its incidence is increasing at an alarming rate (1). Obesity predisposes to the development of nonalcoholic fatty liver disease (NAFLD), which is a spectrum of liver-related pathologies that encompasses steatosis, nonalcoholic steatosis, and nonalcoholic steatohepatitis (2). The development of hepatosteatosis arises as a result of an imbalance between triglyceride deposition and removal. Epidemiologically, NAFLD is associated with type 2 diabetes, suggesting that hepatosteatosis and the development of insulin resistance are causally linked (2). However, both genetic mouse models and clinical data suggest dissociation of hepatosteatosis from insulin resistance, arguing against the existence of such a causal link (3). Several proposed mechanisms have been put forth to explain the relationship between hepatosteatosis and insulin resistance. One mechanism proposes that type 2 diabetes results in hyperinsulinemia, which promotes hepatic lipogenesis and thus hepatosteatosis. Dysfunction in hepatic lipid metabolism and lipotoxicity have also been proposed to activate serine/threonine kinases that subsequently lead to the failure of insulin to signal (4).The actions of kinases in physiological and pathophysiological metabolic pathways have been studied extensively (5, 6). In particular, the mitogen-activated protein kinase (MAPK) pathway is an established regulator of hepatic metabolism (7-10). The stressresponsive MAPK c-Jun NH 2 -terminal kinase 1 (JNK1), when deleted specifically in the liver, results in the development of hepatosteatosis, enhanced hepatic glucose produ...

Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism

“…In contrast to the studies by Vernia et al [22, 23], it has also been reported that p38α/β MAPK, rather than JNK, is involved in the regulation of FGF21 [25]. Mice lacking the expression of MKP-1 in the liver exhibit decreased levels of circulating FGF21 under conditions in which both hepatic p38α/β MAPK and JNK are elevated [25]. Activated mutants of the upstream MAPK kinases for JNK failed to have an effect on a minimal FGF21 promoter but rather a negative regulatory effect on p38α /β MAPK to control FGF21 through a PGC-1α-dependent pathway [25].…”

“…Further evidence for a role for p38α/β MAPK in gluconeogenesis is derived from work studying MKP-1. MKP-1 liver-specific knockout mice exhibit enhanced G6pc and Pck1 , suggesting that MKP-1 negatively regulates gluconeogenesis by opposing p38α/β MAPK- and/or JNK-mediated activation of the gluconeogenic program [25]. These studies establish an important role for hepatic MKP-1 and hence the MAPKs in the regulation of gluconeogenesis (Table 3).…”

“…Hence, it is proposed that hepatic JNK mediates the fasting and feeding cues of circulating FGF21 expression [23]. In contrast to the studies by Vernia et al [22, 23], it has also been reported that p38α/β MAPK, rather than JNK, is involved in the regulation of FGF21 [25]. Mice lacking the expression of MKP-1 in the liver exhibit decreased levels of circulating FGF21 under conditions in which both hepatic p38α/β MAPK and JNK are elevated [25].…”

“…Mice lacking the expression of MKP-1 in the liver exhibit decreased levels of circulating FGF21 under conditions in which both hepatic p38α/β MAPK and JNK are elevated [25]. Activated mutants of the upstream MAPK kinases for JNK failed to have an effect on a minimal FGF21 promoter but rather a negative regulatory effect on p38α /β MAPK to control FGF21 through a PGC-1α-dependent pathway [25]. Hence, hepatic MKP-1, and its effects on p38α /β MAPK appears to play an integral role in the regulation of FGF21 in the liver.…”

“…Furthermore, studies utilizing genetic approaches in mice demonstrate that MKP-1 plays an important role in the dephosphorylation of p38α/β MAPK to negatively regulate hepatic triglyceride metabolism and management of lipid homeostasis [41, 42] (Figure 2). With regards to the role of MKP-1 in obesity, it has been observed that MKP-1 is overexpressed in mice fed a high-fat diet and this correlates with the development of hepatic steatosis [25], suggesting that hepatic p38α/β MAPK declines in states of obesity. Indeed, it has been reported that hepatic p38α/β MAPK activity decreases in mice fed a high-fat diet [43].…”