Cholesterol attenuated the progression of DEN-induced hepatocellular carcinoma via inhibiting SCAP mediated fatty acid de novo synthesis

Dietary and Genetic Cholesterol Loading Rather Than Steatosis Promotes Liver Tumorigenesis and NASH-Driven HCC

“…However, despite this growing evidence there have been diverse studies that indicated a tumor suppressor role of cholesterol in HCC progression [18][19][20][21]. Several mechanisms underlined this suppressor role of cholesterol in HCC, including the sequestration of CD44 in lipid rafts or the inhibition fatty acid de novo synthesis [19].…”

“…For example, through the sequestration of CD44 in lipid rafts, cholesterol inhibits HCC invasion and metastasis [19]. Moreover, cholesterol attenuated the progression of DEN-induced HCC in mice by inhibiting the SCAP-mediated fatty acid de novo synthesis [20], and high serum cholesterol levels increase the antitumor function of natural killer cells, leading to a reduction in the growth of liver tumors [21].…”

STARD1 promotes NASH-driven HCC by sustaining the generation of bile acids through the alternative mitochondrial pathway

“…Next, we addressed the specific contribution of the alternative mitochondrial pathway of BAs generation to HCC. First, we validated the tumor promoter role of cholesterol in HCC because despite accumulating evidence linking cholesterol with HCC development [11][12][13] , there have been studies showing a tumor suppressor effect of cholesterol in HCC [42][43][44][45][46] . As high fat diet (HFD) alone does not induce NASH and the diethylnitrosamine (DEN) plus HFD feeding does not completely model NASH-driven HCC 9 , we established a dietary NASH-driven HCC approach by feeding DENpretreated mice with a HFD diet supplemented with cholesterol (HFHC) (Figure 2A), as this diet has been shown to induce NASH 47,48 .…”

Mitochondrial cholesterol: Metabolism and impact on redox biology and disease

“…For instance, by promoting CD44 localization in lipid rafts, cholesterol impedes HCC invasion and metastasis [ 106 ]. Moreover, cholesterol loading inhibited HCC progression in vivo and in vitro , which was associated with a decreased SCAP (SREBF Chaperone) expression in cholesterol-loaded liver cancer cells [ 107 ]. Unfortunately, these studies did not address the specific contribution of mitochondrial cholesterol, thus raising the possibility that cholesterol may exert a differential role in HCC depending on whether it accumulates in the mitochondrial membrane or extramitochondrial compartments.…”