Hepatocyte Caveolin-1 in NASH mouse models

Introduction:

Caveolin-1 (CAV1) has been proven as an important regulator of lipid accumulation and systemic lipid metabolism. Several animal models have shown that global CAV1 deficiency prevents fat accumulation within hepatocytes, and therewith steatosis. Other data also suggest that altered metabolic liver functions in global CAV1ko mice are caused by adipocytes via paracrine signaling, and hepatocytes subsequently respond to those signals. However, the contribution of hepatocyte CAV1 on pathogenic steatosis has not been investigated before in NASH development and progression. We therefore aimed to analyze the role of CAV1 in the development of steatosis, fibrosis and inflammation in the MCD NASH mouse model.

Methods:

We used hepatocyte specific CAV1ko mice. HepCAV1ko and wildtype littermates were fed an MCD diet for 4 weeks. The role of CAV1 on disease progression was analyzed by quantitative PCR, Western blotting, and immunohistochemistry including H&E, Sirius red, and Oil Red O staining.

Results:

The lipid profile, e.g. triglycerides and cholesterol, was unchanged in serum, as were ALT, AST, ALP and GLDH. In addition, urea, glucose and lactate levels were unchanged in hepCAV1ko compared with wildtype mice. Finally, MCD diet-induced steatosis, fibrosis and inflammation was not affected in hepCAV1ko compared to wildtype mice. However, we found that CAV1 influences apoptosis and inflammation related genes gender dependent after MCD diet. Expression of apoptosis relevant target Bcl2 was upregulated in hepCAV1ko males, but downregulated in females after MCD diet. In context of inflammation, relevant factors such as TNF-alpha, IL1-beta, and IL-6 were similarly distinctly regulated. Significant upregulation was also observed in males, when compared to females in wildtype MCD fed animals.

Conclusion:

Our results demonstrate that hepatocyte specific CAV1 does not affect liver steatosis and fibrosis in NASH, but is playing distinct roles in males and females.