Sphingolipid de novo biosynthesis is essential for intestine cell survival and barrier function

Abstract

Serine palmitoyltransferase (SPT) is the rate-limiting enzyme for sphingolipid biosynthesis. SPT has two major subunits, SPTLC1 and SPTLC2. We previously found that liver Sptlc2 deficiency in early life impairs the development of adherens junctions. Here, we investigated the role of Sptlc2 deficiency in intestine. We treated Sptlc2-Flox/villin-Cre-ERT2 mice with tamoxifen (days 1, 2, and 3) to ablate Sptlc2 specifically in the intestine. At day 6 after tamoxifen treatment, Sptlc2-deficient mice had significantly decreased body weight with concurrent diarrhea and rectal bleeding. The number of goblet cells was reduced in both large and small intestine of Sptlc2-deficient mice compared with controls. Sptlc2 deficiency suppressed the level of mucin2 in the colon and increased circulating lipopolysaccharides, suggesting that SPT activity has a housekeeping function in the intestine. All Sptlc2-deficient mice died 7–10 days after tamoxifen treatment. Notably, supplementation with antibiotics and dexamethasone reduced lethality by 70%. We also found that colon specimens from patients with inflammatory bowel diseases had significantly reduced Sptlc2 expression, SPTLC2 staining, and goblet cell numbers. SPT activity is crucial for intestinal cell survival and barrier function.

The Lipid Status in Patients with Ulcerative Colitis: Sphingolipids are Disease-Dependent Regulated

“…These observations were confirmed by a recently published study showing that the serine palmitoyltrasferase (SPT), which is the rate-limiting enzyme in the sphingolipid de novo synthesis, is essential for intestine cell survival and barrier function [31]. Tamoxifen induced knock down of Sptlc2 in colon epithelial cells lead to diarrhea and rectal bleeding, ending in death after 7–10 days.…”

“…Repression of SPT suppressed the level of ceramides and sphingomyelins in membranes of colon cells, which was accompanied by a reduction of E-cadherin and mucin2 and an induction of apoptosis in the colon. Disruption of the intestinal barrier function came along with an enhanced inflammation and bacterial invasion comparable to IBD in humans [31]. These data emphasize the importance of the sphingolipid de novo synthesis in the colon.…”

“…Recently published studies from human patients suffering from inflammatory bowel disease (UC or Crohn’s disease (CD)) give the first hint that the sphingolipid rheostat is deregulated in UC, however, the data are either generated from stool probes [24] or in untreated patients [25,26]. Furthermore, findings in various mice deficient of an enzyme in the sphingolipid pathway, indicate that sphingolipids play an important role in the development of ulcerative colitis [27,28,29,30,31,32,33,34,35]. These data indicate that the sphingolipid pathway, and especially the balance between different sphingolipids, may impact the development or progression of colitis.…”

CHO/LY-B cell growth under limiting sphingolipid supply: correlation between lipid composition and biophysical properties of sphingolipid-restricted cell membranes+

“…In vivo studies of the SL roles are hampered, among other reasons, by the fact that they can be either synthesized de novo or taken up from the diet. A plausible approach would be to investigate mutant cells containing the smallest possible amounts of SL, or even none at all, but this is not a straightforward procedure because SL appear to be essential for cell growth and survival [2][3][4] . In particular, SL are considered as instrumental in the architecture of eukaryotic cell membranes.…”

Intestinal Acid Sphingomyelinase Protects From Severe Pathogen-Driven Colitis

“…In a porcine model, inhibition of de novo ceramide synthesis impaired the proliferation and barrier function of intestinal epithelial cells, which in turn led to the induction of inflammation (45). Furthermore, intestinal deletion of serine palmitoyltransferase (SPT), which is the rate-limiting enzyme for sphingolipid biosynthesis, significantly decreased the ceramide and sphingomyelin levels in the plasma membrane of gut cells and promoted intestinal cell apoptosis with the impairment of gut barrier function (58). However, further investigation is required to fully understand the impact of Asm on the barrier function in infectious and non-infectious colitis.…”