Hepatocyte-Specific Expression of Human Lysosome Acid Lipase Corrects Liver Inflammation and Tumor Metastasis in lal-/- Mice

The liver is a major organ for lipid synthesis and metabolism. Deficiency of lysosomal acid lipase (LAL; official name Lipa, encoded by Lipa) in mice (lal(-/-)) results in enlarged Liver size due to neutral Lipid storage in hepatocytes and Kupffer cells. To test the functional role of LAL in hepatocyte, hepatocytespecific expression of human LAL (hLAL) in lal(-/-) mice was established by cross-breeding of liveractivated promoter (LAP)-driven tTA transgene and (tet0)(7)-CMV-hLAL transgene with lal(-/-) knockout (KO) (LAP-Tg/K0) triple mice. Hepatocyte-specific expression of hLAL in LAP-Tg/K0 triple mice reduced the liver size to the normal. Level by decreasing lipid storage in both hepatocytes and Kupffer cells. hLAL expression reduced tumor-promoting myeloid-derived suppressive cells in the liver of lal(-/-) mice. As a result, B16 melanoma metastasis to the Liver was almost completely blocked. Expression and secretion of multiple tumor-promoting cytokines or chemokines in the liver were also significantly reduced. Because hLAL is a secretory protein, lal(-/-) phenotypes in other compartments (eg, blood, spleen, and lung) also ameliorated, including systemic reduction of myeloid-derived suppressive cells, an increase in CD4(+) and CD8(+) T and B lymphocytes, and reduced B16 melanoma metastasis in the lung. These results support a concept that LAL in hepatocytes is a critical metabolic enzyme in controlling neutral lipid metabolism, liver homeostasis, immune response, and tumor metastasis.