Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Abstract

Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote expression of Pnpla2/ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning β-oxidation, reflected by increased acylcarnitines (ACs) and reduced β-hydroxybutyrate. This led to elevated plasma free fatty acids (FFAs), which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here, we demonstrate that loss of hepatocyte proliferation is not only an outcome but also possibly a causative factor for liver pathology.

Lipolysis: cellular mechanisms for lipid mobilization from fat stores

“…In hepatocytes, CDK1-dependent phosphorylation of FOXO1 similarly suppresses ATGL expression by cytoplasmic retention of FOXO1. Consistent with this finding, hepatocyte-specific CDK1 deletion induces ATGL-mediated hepatic fat degradation 95 . In contrast, interaction of 14-3-3 proteins with FOXO1 is inhibited by the AMPK-dependent phosphorylation of Ser22 of FOXO1, which enables translocation of this protein to the nucleus 96 .…”

Polyploidy control in hepatic health and disease

“…Elevated ALT (alanine aminotransferase) levels, as well as increased cytokine production and the presence of Kupffer cells were observed already in two weeks old animals [101]. In accordance, a second study showed that Cdk1 deficiency in the liver is accompanied by deregulated lipid metabolism, ultimately leading to hepatic steatosis [118]. These reports suggest that mononuclear polyploidy, a state often referred to as "pathological polyploidy", could by itself produce an inflammatory liver disease.…”

AUP1 regulates lipid metabolism and induces lipid accumulation to accelerate the progression of renal clear cell carcinoma

“…However, de novo FA synthesis is essential to provide the FA required for phospholipid synthesis. 38 In addition, CHOL not only affects the distribution of phospholipids during mitosis but also governs the formation of a vesicular network at the midbody during cytokinesis. 39 In vivo experiments confirmed that the reduction of lipid content, including FA and CHOL, greatly reduces energy supply and biofilm synthesis to maintain cell proliferation, as well as cell cycle arrest and EMT reversal.…”

“…Cell division requires the synthesis of phospholipids that constitute the plasma membrane. However, de novo FA synthesis is essential to provide the FA required for phospholipid synthesis 38 . In addition, CHOL not only affects the distribution of phospholipids during mitosis but also governs the formation of a vesicular network at the midbody during cytokinesis 39 .…”