Activation of c-Jun N-terminal kinase (JNK) has been implicated as a mechanism in the development of steatohepatitis. This finding, together with the reported role of JNK signaling in the development of obesity and insulin resistance, two components of the metabolic syndrome and predisposing factors for fatty liver disease, suggests that JNK may be a central mediator of the metabolic syndrome and an important therapeutic target in steatohepatitis. To define the isoform-specific functions of JNK in steatohepatitis associated with obesity and insulin resistance, the effects of JNK1 or JNK2 ablation were determined in developing and established steatohepatitis induced by a high-fat diet (HFD). HFD-fed jnk1 null mice failed to develop excessive weight gain, insulin resistance, or steatohepatitis. In contrast, jnk2 Ψ/Ψ mice fed a HFD were obese and insulin-resistant, similar to wild-type mice, and had increased liver injury. In mice with established steatohepatitis, an antisense oligonucleotide knockdown of jnk1 decreased the amount of steatohepatitis in concert with a normalization of insulin sensitivity. Knockdown of jnk2 improved insulin sensitivity but had no effect on hepatic steatosis and markedly increased liver injury. A jnk2 knockdown increased hepatic expression of the proapoptotic Bcl-2 family members Bim and Bax and the increase in liver injury resulted in part from a Bim-dependent activation of the mitochondrial death pathway. Conclusion: JNK1 and JNK2 both mediate insulin resistance in HFD-fed mice, but the JNK isoforms have distinct effects on steatohepatitis, with JNK1 promoting steatosis and hepatitis and JNK2 inhibiting hepatocyte cell death by blocking the mitochondrial death pathway. (HEPATOLOGY 2009;49:87-96.) See Editorial on Page 6
T he hepatocellular mechanisms underlying the development of steatosis and the progression to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) remain unclear. 1 A critical factor in the pathogenesis of this disease is thought to be the existence of insulin resistance, and NAFLD can be considered a component of the metabolic syndrome, whose manifestations also include obesity and diabetes. Recent investigations have suggested that activation of the mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) is a central mechanism for the development of obesity and insulin resistance as well as for steatohepatitis. 4-7 JNK may therefore represent a unique common target for the therapy of a variety of diseases that comprise the metabolic syndrome, but whether an inhibition of JNK function will decrease or prevent further progression of established steatohepatitis is currently unknown.
Most cells including hepatocytes express two JNK genes, jnk1 and jnk2, which are alternatively spliced to yield β£ and β€ forms of both a p54 and p46 protein. Recent studies have demonstrated that the JNK isoforms differ in function as exemplified by the ability of JNK1 to phosphorylate and activate the transcription factor c-Jun, whereas JNK2 lacks this activity and may even oppose this action of JNK1. 9 Our prior studies have implicated JNK signaling in the development of steatohepatitis. First, it was demonstrated that hepatocyte overexpression of the prooxidant enzyme cytochrome P450 2E1 as occurs in