Lipid droplet turnover at the lysosome inhibits growth of hepatocellular carcinoma in a BNIP3-dependent manner

Hepatic steatosis is a major etiological factor in hepatocellular carcinoma (HCC), but factors causing lipid accumula-tion leading to HCC are not understood. We identify BNIP3 (a mitochondrial cargo receptor) as an HCC suppressor that mitigates against lipid accumulation to attenuate tumor cell growth. Targeted deletion of Bnip3 decreased tumor latency and increased tumor burden in a mouse model of HCC. This was associated with increased lipid in bnip3-/- HCC at early stages of disease, while lipid did not accumulate until later in tumorigenesis in wild-type mice, as Bnip3 expression was attenuated. Low BNIP3 expression in human HCC similarly correlated with increased lipid content and worse prognosis than HCC expressing high BNIP3. BNIP3 suppressed HCC cell growth by promoting lipid droplet turnover at the lysosome in a manner dependent on BNIP3 binding LC3. We have termed this process mitolipophagy because it involves the coordinated autophagic degradation of lipid droplets with mitochondria.

Automated summary

Hepatic steatosis is a major factor in the development of hepatocellular carcinoma (HCC). In this study, BNIP3, a mitochondrial cargo receptor, was identified as a suppressor of HCC that reduces lipid accumulation and inhibits tumor cell growth. Deletion of Bnip3 in a mouse model of HCC resulted in shorter tumor latency and increased tumor burden, accompanied by early lipid accumulation. Low BNIP3 expression in human HCC was also associated with increased lipid content and worse prognosis.