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Updated: Aug 20, 2025
Inducing and Characterizing Vesicular Steatosis in Differentiated HepaRG Cells
Published on: July 18, 2019
Hepatic DKK1-driven steatosis is CD36 dependent
Zhen Yang1,2, Xinping Huang1,2, Jiaye Zhang1
1Center for Health Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Abstract:
Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide; about 25% of NAFLD silently progress into steatohepatitis, in which some of them may develop into fibrosis, cirrhosis and liver failure. However, few drugs are available for NAFLD, partly because of an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of-function approaches, we identified up-regulated DKK1 plays a pivotal role in high-fat diet-induced NAFLD and its progression. Mechanistic analysis reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through the ERK-PPARγ-CD36 axis. Moreover, DKK1 increased insulin resistance by activating the JNK signaling, which in turn exacerbates disorders of hepatic lipid metabolism. Our finding suggests that DKK1 may be a potential therapeutic and diagnosis candidate for NAFLD and metabolic disorder progression.
Insights
DKK1 is a key player in nonalcoholic fatty liver disease (NAFLD) progression. This study reveals DKK1 promotes fatty acid uptake and insulin resistance, suggesting it as a therapeutic target for NAFLD.
Area of Science:
- Hepatology
- Metabolic Disorders
- Molecular Biology
Background:
- Nonalcoholic fatty liver disease (NAFLD) affects a significant portion of the global population.
- Disease progression from NAFLD to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and liver failure is poorly understood, limiting therapeutic options.
- Incomplete knowledge of NAFLD pathogenesis hinders the development of effective treatments.
Purpose of the Study:
- To investigate the role of Dickkopf-1 (DKK1) in the development and progression of high-fat diet-induced NAFLD.
- To elucidate the molecular mechanisms by which DKK1 influences hepatic lipid metabolism and insulin resistance.
Main Methods:
- Employed in vivo and in vitro gain- and loss-of-function studies.
- Utilized mechanistic analysis to explore signaling pathways involved in DKK1 function.
- Investigated the impact of DKK1 on fatty acid uptake and insulin signaling.
Main Results:
- Identified up-regulated DKK1 as a critical factor in high-fat diet-induced NAFLD.
- DKK1 enhances hepatocyte fatty acid uptake via the ERK-PPARγ-CD36 pathway.
- DKK1 exacerbates hepatic lipid metabolism disorders and insulin resistance by activating JNK signaling.
Conclusions:
- DKK1 plays a pivotal role in the pathogenesis and progression of NAFLD.
- Targeting DKK1 may offer a novel therapeutic strategy for NAFLD.
- DKK1 could serve as a diagnostic marker for NAFLD and associated metabolic disorders.
