Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver

Objectives

Prior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions.

Methods

Mice with or without hepatocyte cyclin D1 (D1 ^fl/fl or D1 ^ΔHep ) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. The C. elegans model was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition.

Results

Cyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1 ^ΔHep mice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroid Ercc1 -deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine of Caenorhabditis elegans (which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting.

Conclusions

Cyclin D1 regulates nutrient-mediated physiology in the liver and C. elegans , indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging.

Highlights

• Cyclin D1 is induced in hepatocytes with feeding and broadly regulates hepatic gene expression.

• Acute phase response (APR) and senescence-associated secretory phenotype (SASP) proteins are markedly regulated by cyclin D1.

• Hepatocyte expression of cyclin D1 is substantially upregulated in aging, premature aging, and MASLD without associated proliferation.

• Cyclin D1 (CYD-1) regulates nutrient-mediated signaling and lifespan in response to overnutrition in C. elegans .