JNK regulation of hepatic manifestations of the metabolic syndrome

Abstract

Nonalcoholic fatty liver disease (NAFLD) is now recognized as both an important component of the metabolic syndrome and the most prevalent liver disease in the United States. Although the mechanisms for development of steatosis and chronic liver injury in NAFLD remain unclear, recent investigations have indicated that overactivation of c-Jun N-terminal kinase (JNK) is critical to this process. These findings, together with evidence for the involvement of JNK signaling in other manifestations of the metabolic syndrome such as obesity and insulin resistance, have suggested that JNK may be a novel therapeutic target in this disorder. This review details findings that JNK mediates lipid accumulation and cell injury in fatty liver disease and discusses the possible cellular mechanisms of JNK actions. Nonalcoholic fatty liver disease is an important component of the metabolic syndromeThe metabolic syndrome has been defined classically by the clinical features of obesity, glucose intolerance, dyslipidemia and hypertension [1]. This disorder is highly prevalent, affecting 50 million people in the United States alone, and its incidence is increasing with the rising rates of obesity and diabetes. The metabolic syndrome is a significant cause of morbidity and an independent predictor of mortality in older adults [2]. Although interest has largely focused on cardiovascular complications resulting from accelerated atherosclerosis [3], the importance of increased lipid accumulation in other organs that characterizes the metabolic syndrome is now being recognized. One such manifestation is nonalcoholic fatty liver disease (NAFLD) [4]. NAFLD contributes to the morbidity and mortality of the metabolic syndrome, and one long-term study demonstrated a higher mortality rate in type 2 diabetics from liver disease than cardiovascular disease [5]. In addition to effects from the actual liver disease, fatty liver and the associated hepatic insulin resistance contribute to the metabolic syndrome because of the liver's central role in glucose and lipid homeostasis. The presence of liver injury predicts the development of cardiovascular disease [6,7], suggesting a central function for NAFLD in clinical manifestations of the metabolic syndrome.

Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα

“…Although this inconsistency in mechanism for cancer and metabolic disorders currently remains unexplored, the downstream signaling activated by periostin might be cell or tissue specific. In addition, studies using genetically engineered mice have shown that hyperactivation of the JNK pathway contributes to the development of metabolic diseases, including hepatic steatosis, obesity, and insulin resistance (36)(37)(38). Consistent with this, strong activation of JNK has been observed in the livers of HFD-fed mice and genetically obese mice (39,40).…”

Increased expression of c-Jun in nonalcoholic fatty liver disease

“…It is important to distinguish interruption of hyperactivation of hepatocellular JNK/c-Jun/ AP-1 signaling from a complete abolishment of JNK in hepatocytes, as mice with specific ablation of Jnk1 in hepatocytes surprisingly exhibit glucose intolerance, insulin resistance and hepatic steatosis. 9 Moreover, we have shown that c-Jun abundance is a critical pathogenic factor in malignant melanoma independent of JNK activation. 56 There, c-Jun levels are regulated at the post-transcriptional level by micro RNA (miR) 125b.…”

“…Surprisingly, we found enhanced c-Jun levels, and this observation was confirmed in human tissues, too. The activity of c-Jun N-terminal kinases (JNKs) and herewith c-Jun activation have been implicated in NASH progression, 8,9 but abundance of c-Jun in NAFLD has not been describe before.…”

Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver

“…In contrast to 3 mo, 7 mo-long high fat intake increased aSMA expression in the livers of both floxed and knockout mice ( Figure 7A). Studies with JNK knockout mice fed with methioninecholine-deficient diet (MCD) diets have indicated a role for c-Jun N-terminal kinase (JNK) in steatosis [42] . JNK is activated by phosphorylation on serine residues [43] .…”