Tumor Progression Locus 2 in Hepatocytes Potentiates Both Liver and Systemic Metabolic Disorders in Mice
Jun Gong1,2, Chun Fang3,2,4, Peng Zhang3,2,4
1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.
Abstract:
Tumor progression locus 2 (TPL2), a serine/threonine kinase, has been regarded as a potentially interesting target for the treatment of various diseases with an inflammatory component. However, the function of TPL2 in regulating hepatocyte metabolism and liver inflammation during the progression of nonalcoholic fatty liver disease (NAFLD) is poorly understood. Here, we report that TPL2 protein expression was significantly increased in fatty liver from diverse species, including humans, monkeys, and mice. Further investigations revealed that compared to wild-type (WT) littermates, hepatocyte-specific TPL2 knockout (HKO) mice exhibited improved lipid and glucose imbalance, reserved insulin sensitivity, and alleviated inflammation in response to high-fat diet (HFD) feeding. Overexpression of TPL2 in hepatocytes led to the opposite phenotype. Regarding the mechanism, we found that mitogen-activated protein kinase kinase 7 (MKK7) was the specific substrate of TPL2 for c-Jun N-terminal kinase (JNK) activation. TPL2-MKK7-JNK signaling in hepatocytes represents a promising drugable target for treating NAFLD and associated metabolic disorders. Conclusion: In hepatocytes, TPL2 acts as a key mediator that promotes both liver and systemic metabolic disturbances by specifically increasing MKK7-JNK activation.
Insights
Tumor progression locus 2 (TPL2) promotes metabolic dysfunction and liver inflammation in nonalcoholic fatty liver disease (NAFLD). Inhibiting TPL2 may offer a therapeutic strategy for NAFLD and related metabolic disorders.
Area of Science:
- Biochemistry
- Molecular Biology
- Hepatology
Background:
- Tumor progression locus 2 (TPL2) is a kinase implicated in inflammatory diseases.
- Its role in nonalcoholic fatty liver disease (NAFLD) pathogenesis, particularly in hepatocyte metabolism and liver inflammation, remains unclear.
Purpose of the Study:
- To investigate the function of TPL2 in regulating hepatocyte metabolism and liver inflammation during NAFLD progression.
- To elucidate the underlying molecular mechanisms involving TPL2 in NAFLD.
Main Methods:
- Analysis of TPL2 protein expression in fatty liver across species (humans, monkeys, mice).
- Generation and assessment of hepatocyte-specific TPL2 knockout (HKO) mice fed a high-fat diet (HFD).
- Investigation of TPL2's role in mitogen-activated protein kinase kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK) activation.
Main Results:
- TPL2 protein expression is elevated in fatty liver across species.
- Hepatocyte-specific TPL2 knockout mice showed improved lipid/glucose balance, insulin sensitivity, and reduced inflammation under HFD.
- TPL2 directly activates MKK7-JNK signaling in hepatocytes, exacerbating metabolic disturbances.
Conclusions:
- TPL2 is significantly upregulated in NAFLD and acts as a key mediator of liver and systemic metabolic dysfunction.
- The TPL2-MKK7-JNK pathway in hepatocytes is a critical driver of NAFLD pathogenesis.
- Targeting TPL2-MKK7-JNK signaling presents a potential therapeutic avenue for NAFLD and associated metabolic disorders.
Related Concept Videos
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
01:26Locus of Control
00:52What is Metabolism?
01:19Root-Locus Method
This system can be represented by a block...
01:15Construction of Root Locus
For positive gain values, the root locus exists on the real axis to the left of an odd number of finite open-loop poles or zeros. The root locus starts at the open-loop poles and traces the paths of the closed-loop poles as the gain...
01:05Properties of the Root Locus
To determine if a point lies on the root locus, the criterion involves the sum of angles contributed by all poles and zeros to that point. Specifically, this sum must be an odd multiple of 180 degrees. The gain at any point on...