Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high‐fat diet

Abstract

Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH‐mediated liver cirrhosis and HCC are lacking. Cholesterol is closely associated with vascular endothelial growth factor (VEGF), a key factor that promotes HCC. Recent reports have demonstrated that statins could prevent HCC development. In contrast, we have little information on ezetimibe, an inhibitor of cholesterol absorption, in regards to the prevention of NASH‐related liver cirrhosis and HCC. In the present study, a steatohepatitis‐related HCC model, hepatocyte‐specific phosphatase and tensin homolog (Pten)‐deficient (Pten Δhep) mice were fed a high‐fat (HF) diet with/without ezetimibe. In the standard‐diet group, ezetimibe did not reduce the development of liver tumors in Pten Δhep mice, in which the increase of serum cholesterol levels was mild. Feeding of a HF diet increased serum cholesterol levels markedly and subsequently increased serum levels of VEGF, a crucial component of angiogenesis. The HF diet increased the number of VEGF‐positive cells and vascular endothelial cells in the tumors of Pten Δhep mice. Kupffer cells, macrophages in the liver, increased VEGF expression in response to fat overload. Ezetimibe treatment lowered cholesterol levels and these angiogenetic processes. As a result, ezetimibe also suppressed inflammation, liver fibrosis and tumor growth in Pten Δhep mice on the HF diet. Tumor cells were highly proliferative with HF‐diet feeding, which was inhibited by ezetimibe. In conclusion, ezetimibe suppressed development of liver tumors by inhibiting angiogenesis in Pten Δhep mice with hypercholesterolemia.

Eight key long non-coding RNAs predict hepatitis virus positive hepatocellular carcinoma as prognostic targets

“…No study had investigated the biological functions for the eight lncRNAs identified in HCC; however, they could affect the genesis as well as the progression of HCC by the Wnt signaling pathway[20-24], angiogenesis[25,26], p53 pathway[27,28], and PI3 kinase pathways[29-31], as suggested by the pathway enrichment results. More importantly, this research could provide new evidence that lncRNAs, whose biological functions had not been reported before, might potentially serve as the potent markers to predict the prognosis of HCC.…”

Angiogenic inflammation and formation of necrosis in the tumor microenvironment influence patient survival after radical surgery for de novo hepatocellular carcinoma in non-cirrhosis

“…Of note, NASH-driven hepatocarcinogenesis is mechanistically involved in the process of necrosis formation in the tumor microenvironment, and the latter has also been related to enhanced infiltration with immune-competent cells [5][6][7][8][9]. Furthermore, experimental studies reported on novel angiogenic pathways playing a key role in de novo or NASH-driven hepatocarcinogenesis, implicating the complex immunologic mechanisms involved in cancer progression [10][11][12][13].…”

Prognostic Values of Stabilin-2 in Hepatocellular Carcinoma

“…Non-alcoholic steatohepatitis (NASH) is a common cause of cirrhosis and hepatocellular carcinoma (HCC). Studies have shown that a high-fat diet promotes serum cholesterol levels in mice liver, subsequently increases vascular endothelial-derived growth factor (VEGF) levels, and ultimately leads to high proliferation of liver tumor cells [49]. STAB2 acts as a scavenger receptor and is implicated in cell apoptosis [50].…”