Blockage of sphingolipid de novo synthesis pathway (through knockout
Serine Palmitoyltransferase, the key enzyme in the pathway) impairs
hepatocyte polarity, attenuates liver regeneration after hepatectomy,
and promotes tumorigenesis, revealed a new research led by SUNY Downstate Medical Center.
Almost all cell types exhibit some sort of polarity, which enables
them to carry out specialized functions. Adherens junctions, which
consist of the transmembrane protein cadherin and the intracellular
components beta-catenin, alpha-catenin, and actin filaments, initiate
cell-cell contacts and maintenance of cell polarity.
‘Blockage of sphingolipid de novo synthesis pathway impairs hepatocyte polarity, attenuates liver regeneration after hepatectomy.’
Because all cell
membranes that define cell boundaries and polarity contain lipid
bi-layer structures, the lipid, including sphingolipid, environment
could influence polarity, yet the mechanism underlying this remission is
Importantly, the deficiency significantly
reduces sphingomyelin but not other sphingolipids in hepatocyte plasma
membrane, and greatly reduces cadherin, the major protein in adherens
junctions, on the membrane. The deficiency affects cellular distribution
of b-catenin, the central component of the canonical Wnt pathway.
Furthermore, such a defect can be partially corrected by
sphingomyelin supplementation in vivo and in vitro. SUNY Downstate's
Professor of Cell Biology Xian-Cheng Jiang and Assistant Professor
of Surgery Chongmin Huan are co-corresponding authors of the
article detailing the research.
Dr. Jiang explained, "This was a seven-year effort and a
breakthrough linking sphingolipid-mediated cell junctions and
tumorigenesis. Our results, for the first time, show that plasma
membrane sphingomyelin-related b-catenin cellular distribution is one
the key factors in regulating hepatocyte polarity and tumorigenesis."
Dr. Jiang concludes, "This study also will provide a guide for the
development of serine palmitoyltransferase inhibitors, which have a
potential for the treatment of metabolic diseases such as diabetes."