BNIP3 attenuates hepatocellular carcinoma by promoting lipid droplet turnover at the lysosome.

Abstract

Hepatic steatosis is a major etiological factor in hepatocellular carcinoma (HCC). Work reported here identifies BNIP3 as a suppressor of HCC that mitigates against lipid accumulation. Loss of BNIP3 decreased tumor latency and increased tumor burden in a mouse model of HCC. This was associated with increased lipid accumulation and elevated HCC tumor cell growth. Conversely, exogenous BNIP3 decreased lipid levels and reduced HCC tumor cell growth. Mutant BNIP3W18A that is unable to promote mitophagy did not decrease HCC cell growth and was defective at reducing lipid levels. Growth suppression by BNIP3 was not mediated by effects on fatty acid oxidation (FAO) or de novo lipogenesis (DNL). Rather, BNIP3 suppressed HCC cell growth by promoting lipid droplet turnover at the lysosome through a process we have termed “mitolipophagy” in which lipid droplets and mitochondria are turned over together at the lysosome. Low BNIP3 expression in human HCC also correlated with increased lipid content and worse prognosis than HCC expressing high levels of BNIP3. This work reveals a role for BNIP3 and lipid droplet turnover at the lysosome in attenuating HCC.