Obesity-associated deoxycholic acid promotes hepatocellular carcinoma by provoking senescence associated secretory phenotype in hepatic stellate cells via the mTOR signaling pathway
Lamees El Nihum
Introduction. Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and third in cancer-related death1. Five-year survival rates of patients undergoing curative therapies including liver transplant and hepatic resection range between 40-75%1. Hepatic fibrosis, a response to chronic inflammation, is the strongest predisposing factor for HCC and increasingly caused by obesity-induced non-alcoholic fatty liver disease1,2. Obesity-associated rise of Gram-positive bacteria in the GI tract promotes enterohepatic circulation of gut bacterial metabolites including the secondary bile acid deoxycholic acid (DCA)3,4,5. DCA induces senescence in hepatic stellate cells, which remain metabolically active with a pro-inflammatory secretome termed the senescence associated secretory phenotype (SASP)6,7. Persistent inflammation triggers transformation of damaged hepatocytes, leading to cancer7. Methods. DMBA-administered mice were fed a normal diet (ND) or high-fat diet (HFD) for 30 weeks3. Gut bacterial populations were determined by assessing fecal matter, serum DCA recorded and antibiotics treatment performed3. Post-mortem distribution of tumors and biomarker evidence of HSC activation were analyzed3. The experiment was elaborated further by treating HFD mice at 13 weeks onwards with antibiotics with or without DCA feeding3. In another study, western blot analysis analyzed phosphorylation of mTOR in HFD versus ND mice8. Results. HCC lesions with senescent HSCs, marked by the presence of senescence markers such as p21Waf1/Cip1 and p16INK4a and DNA damage markers 53BP1 and γ-H2AX, were observed in HFD mice3. A substantial increase in Gram-positive Clostridium cluster XI and XIVa was observed in HFD mice3. Serum DCA was substantially increased in HFD mice and fell with vancomycin treatment3. Tumor suppression in DCA-fed HFD mice was enhanced significantly by a combination of four antibiotics compared to vancomycin only3. HCC and SASP were observed in DCA-fed HFD mice with and without the presence of antibiotics, implying that DCA alone can provoke HCC in HFD mice without the presence of Gram-positive bacteria; however, DCA alone was insufficient to enhance HCC in ND mice3. This suggests that an additional obesity-associated factor, such as increased gut permeability, exists to promote obesity-associated HCC3,9. mTOR phosphorylation was significantly elevated in HFD mice and suppressed with antibiotics, suggesting that hepatic mTOR activation is mediated by gut microbiota-generated deoxycholic acid8. Conclusions. Genetically obese ND mice show high levels of DCA, implying that obesity, not HFD, causes HCC3,4. The precise mechanism by which deoxycholic acid initiates mTOR and the oncogenic process in the liver remains unclear8. Deoxycholic acid-induced HCC is likely augmented by obesity-induced pro-inflammatory changes in the liver8.
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