c-Jun NH2-terminal kinase 1 in hepatocytes: An essential mediator of insulin resistance


  • Potential conflict of interest: Nothing to report.

Sabio G, Cavanagh-Kyros J, Ko HJ, Jung DY, Gray S, Jun JY, et al. Prevention of steatosis by hepatic JNK1. Cell Metab 2009;10:491-498. (Reprinted with permission.)


Nonalcoholic steatosis (fatty liver) is a major cause of liver dysfunction that is associated with insulin resistance and metabolic syndrome. The cJun NH2-terminal kinase 1 (JNK1) signaling pathway is implicated in the pathogenesis of hepatic steatosis and drugs that target JNK1 may be useful for treatment of this disease. Indeed, mice with defects in JNK1 expression in adipose tissue are protected against hepatic steatosis. Here we report that mice with specific ablation of Jnk1 in hepatocytes exhibit glucose intolerance, insulin resistance, and hepatic steatosis. JNK1 therefore serves opposing actions in liver and adipose tissue to both promote and prevent hepatic steatosis. This finding has potential implications for the design of JNK1-selective drugs for the treatment of metabolic syndrome.


Nonalcoholic fatty liver disease (NAFLD) affects 10% to 29% of the world population. Even though scientists and clinicians have increased their activity to understand the development of steatosis and its progression to steatohepatitis, the complex hepatocellular mechanisms underlying the disease remain unclear.1-3 A critical feature of the pathogenesis is metabolic syndrome, the manifestations of which include obesity and type 2 diabetes mellitus associated with strong and abnormal inflammatory responses.4-6 It is well documented that proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) are produced during the course of obesity and are involved in triggering insulin resistance; this is consistent with the fact that anti-inflammatory drugs promote insulin sensitivity.7

TNF and free fatty acids are powerful regulators of the activity of c-Jun NH2-terminal kinase (JNK) and IkappaB kinase (I-κB), two central kinases involved in coupling inflammatory and metabolic signals.7 JNK activation increases the phosphorylation of insulin receptor substrate-1 (IRS-1) on serine 307 and thus inhibits binding to the insulin receptor.7, 8 This association between JNK activation and the inhibitory phosphorylation of the adaptor protein IRS-1 provides a direct molecular link between JNK and insulin resistance.9

Many studies have led to the hypothesis that JNK is pivotal to the development of insulin resistance, obesity, and metabolic syndrome.10 Among the three JNK isoforms, JNK1 and JNK2 are broadly expressed, whereas JNK3 is predominantly expressed in the heart, testes, and brain.11 Therefore, JNK1 and JNK2 expression levels mainly determine total JNK activity in fat-loaded tissues such as the liver.

The liver represents a site of metabolic regulation by JNK1. Striking evidence for a role of JNK1 in NAFLD comes from the finding that patients with type 2 diabetes, leptin-deficient (ob/ob) mice (genetically prone to obesity), and mice fed either a high-fat diet or a methionine and choline–deficient diet exhibit high JNK1 activity in their liver, skeletal muscle, and fat.12, 13 The generation of JNK1 knockout mice resulted in enthusiasm in the scientific community. In different models, these mice showed lower body weight gain, body fat content, and plasma glucose and insulin levels along with enhanced insulin-signaling activity.12, 14, 15

The feeding of JNK1-deficient mice with steatosis-inducing diets is limited. These mice develop hepatic insulin resistance, but these models lack the human NAFLD features of obesity, collagen deposition, and peripheral insulin resistance; this renders these studies problematic for assessing the relative tissue-specific contribution of JNK1 to insulin resistance.11 To overcome this issue, Brenner et al.16 fed a choline-deficient L-amino acid–defined diet to chimeric mice in which only the hematopoietic compartment was replaced by wild-type, JNK1−/−, or JNK2−/− cells. This diet is only choline-deficient and thus is ideal for studying the sequential progression of steatohepatitis producing human NAFLD. This work is important because Kodama et al.16 demonstrated that JNK1 in hematopoietic (non–insulin-producing) cells is indispensable for hepatic steatosis–induced inflammation by Kupffer cell activation.

To better define the tissue-specific function of JNK1, in vivo knockdown in mice has been assessed with different experimental approaches. Antisense oligonucleotides,1 adenovirus-mediated delivery of JNK1 short hairpin RNA,11 and transgenic expression of a mitogen-activated protein kinase phosphatase (dual specificity phosphatase 9)17 suppress JNK activation. Collectively, these approaches demonstrate increased insulin sensitivity, loss of susceptibility to hepatic steatosis, and reduced hepatic triglyceride content concomitant with decreased liver injury and cell death.1, 13

Recently, Davis' group established conditional JNK1 knockout animals. These animals are a major breakthrough for better defining the tissue-specific role of JNK1 in the pathophysiology of obesity-related diseases.18, 19 In the present report,20 the group used hepatocyte-specific JNK1 knockout (JNK1Δhepa) mice. Interestingly, these mice exhibited glucose intolerance in contrast to several previous studies employing intravenous delivery of adenoviruses.11, 21 Potentially, these differences can be explained by the disruption of JNK1 signaling in different cell types because this approach lacks absolute hepatocyte specificity. Additionally, JNK1Δhepa mice showed decreased hepatic protein kinase B (AKT) activation associated with reduced insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1. They also found triglyceride accumulation linked to increased dietary lipid absorption, decreased fat oxidation, and/or increased lipogenesis. Thus, de novo lipogenesis may contribute to steatosis in JNK1Δhepa mice. Indeed, livers from these mice exhibited increased expression of genes that promote hepatic lipogenesis, such as peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β; a key activator of hepatic lipogenesis) and sterol regulatory element binding protein 1 (SREBP1), and a concomitant increase in microsomal triacylglycerol transfer protein (MTP). The important role of MTP for lipoprotein assembly has also been confirmed by other studies.11, 22, 23

In Fig. 1, the existing data and the conclusions taken from Sabio et al.'s report20 are depicted, and the important role of JNK1 in metabolic syndrome is shown. Insulin resistance represents a central characteristic of type 2 diabetes. Free fatty acids and proinflammatory cytokines (e.g., TNF) modulate JNK1 activity. JNK1 activation increases IRS-1 phosphorylation and prevents its interaction with the insulin receptor; this results in insulin resistance. Additionally, JNK1 controls activator protein 1 (AP-1) transcription; this increases the expression of proinflammatory mediators and cell death. Moreover, activation of the SREBP1 pathway, which promotes hepatic lipogenesis, and increased expression of forkhead box O1 (FOXO1) and the coactivator PGC1α seem to contribute to gluconeogenesis in this scenario in concert with increased levels of triglycerides, which promote hepatic steatosis. Fifty percent of the insulin newly secreted by pancreatic β-cells into the portal vein is internalized and degraded by the liver, the main site of insulin clearance. Disease progression from metabolic syndrome to type 2 diabetes is triggered by the failure of pancreatic β-cells due to exhaustion.

Figure 1.

Proposed mechanism for the activation of JNK1 in insulin resistance and hepatic steatosis. Free fatty acids and proinflammatory cytokines such as TNF modulate JNK1 activity. Activation of JNK1 increases phosphorylation of IRS-1 and prevents the binding of IRS with its receptor; this promotes insulin resistance, hepatic steatosis, and cell death through activation of a caspase signaling pathway. In addition, activation of the SREBP1 pathway, which promotes hepatic lipogenesis, and increased expression of FOXO1 and the coactivator PGC1α could contribute to gluconeogenesis concomitant with increased levels of triglycerides. Finally, JNK1 controls transcriptional activation of AP-1 and thus increases expression of proinflammatory cytokines and contributes to JNK1 activation.

In summary, the function of JNK1 in hepatocytes seems to be of the utmost importance because it is an essential regulator of liver metabolism directly associated with the development of insulin resistance, glucose intolerance, and hepatic steatosis. The design of effective therapies targeting JNK1 will represent a therapeutic advance for the treatment of the pathophysiology of metabolic syndrome.