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Incorporation of a Survivable Liver Biopsy Procedure in Mice to Assess Non-alcoholic Steatohepatitis NASH Resolution
Published on: April 16, 2019
Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice
Zhiqiang Fang1, Hao Xu1, Juanli Duan1
1Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
Abstract:
Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has never been elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. In male and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, and improved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulin resistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. In addition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifen treatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice with metabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeutic effect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathway was inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen in treating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner.
Insights
Tamoxifen shows promise for treating nonalcoholic fatty liver disease (NAFLD) by reducing liver fat and improving insulin sensitivity. Its therapeutic effects are linked to the JNK/MAPK pathway, independent of gender or estrogen receptors.
Area of Science:
- Hepatology
- Pharmacology
- Molecular Biology
Background:
- Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with limited effective treatments.
- Tamoxifen, a known chemotherapy agent, has not been previously investigated for its potential in treating NAFLD.
Purpose of the Study:
- To investigate the therapeutic potential of tamoxifen in nonalcoholic fatty liver disease (NAFLD).
- To elucidate the underlying mechanisms of tamoxifen's action in NAFLD, including its dependence on gender and estrogen receptors.
Main Methods:
- In vitro studies using hepatocytes exposed to sodium palmitate.
- In vivo experiments with male and female mice models of NAFLD.
- RNA sequencing to identify affected signaling pathways.
- Pharmacological manipulation of the JNK/MAPK pathway.
Main Results:
- Tamoxifen protected hepatocytes from lipotoxicity in vitro.
- Continuous tamoxifen administration inhibited hepatic lipid accumulation and improved glucose/insulin intolerance in mice.
- Short-term tamoxifen improved hepatic steatosis and insulin resistance but not inflammation or fibrosis.
- Tamoxifen's effects were independent of gender and estrogen receptor status.
- Tamoxifen inactivated the JNK/MAPK signaling pathway, which was crucial for its therapeutic benefits.
Conclusions:
- Tamoxifen demonstrates therapeutic potential for NAFLD by improving key disease markers.
- The JNK/MAPK signaling pathway mediates tamoxifen's beneficial effects in NAFLD.
- Tamoxifen represents a potential novel therapeutic strategy for NAFLD, warranting further clinical investigation.
