Effect of SPTLC3 on aging- and diet-induced insulin resistance and atherosclerosis

The National Heart, Lung, and Blood Institute awarded The Research Foundation For The State University Of New York (doing business as SUNY Downstate Health Sciences University) $799,659 on August 1, 2026, as a Project Grant under the Cardiovascular Diseases Research program (CFDA 93.837).

The recipient will conduct research on the effect of SPTLC3 (serine palmitoyltransferase long-chain base subunit 3) on aging- and diet-induced insulin resistance and atherosclerosis. The work examines the role of SPTLC3 in sphingolipid biosynthesis and its relationship to metabolic diseases in aged organisms, with emphasis on high-fat-diet-induced pathology. The research uses global SPTLC3 knockout mouse models to determine whether SPTLC3, distinct from related subunits SPTLC1 and SPTLC2, is crucial for sphingolipid biosynthesis and serves as a key factor in diet-induced metabolic dysfunction. Preliminary findings indicate age-dependent and diet-responsive SPTLC3 expression in liver and adipose tissues of mice, primates, and humans, providing a foundation for mechanistic investigation.

Performance occurs in Brooklyn, New York 11203. The period of performance runs from August 1, 2026, through April 30, 2030. The Research Foundation For The State University Of New York, operating as Sponsored Programs Office - System Administration, serves as the parent administrative entity. No sub-recipients are identified in the source material.

Abstract

Serine palmitoyltransferase (SPT), the key enzyme for DE novo sphingolipid synthesis, is a promising target for pharmacological intervention in insulin resistance, metabolic dysfunction-associated fatty liver disease (MAFLD), dyslipidemia, and atherosclerosis. However, the molecular basis of SPT-mediated effects is not well understood. Mammalian SPT comprises two subunits, SPTLC1 and SPTLC2, but there is a third subunit, SPTLC3. As our previous studies on SPT focused on SPTLC1 and SPTLC2, the function of SPTLC3 is largely unknown. Several human genome-wide association studies clearly indicate that SPTLC3, but not SPTLC1 or SPTLC2, correlates strongly with metabolic diseases. However, SPTLC3 mrna levels are barely detectable in major metabolic tissues, such as the liver and adipose tissues of adult mice less than 5 months old. Our preliminary results showed age-dependent expression of SPTLC3, but not SPTLC1 or SPTLC2, in the liver and adipose tissues of both male and female mice. Further, we found that a high-FAT diet increased SPTLC3 expression. Importantly, we also found age-dependent SPTLC3 expression in the liver of humans, and a high-FAT diet promoted SPTLC3 expression in the liver of middle-aged monkeys. As most human metabolic diseases are related to aging and/or high-FAT diets, our new findings provide a solid foundation for our proposed studies on SPTLC3. We determined that, unlike global SPTLC1 or SPTLC2 knockout (KO) mice, global SPTLC3 KO mice are viable and healthy. The availability of mouse models provides US with unique tools to determine the relationship between SPTLC3 and metabolic diseases in aged mice. We hypothesize that: 1) SPTLC3, but not SPTLC1 or SPTLC2, is crucial for sphingolipid biosynthesis in aged mice and humans; and 2) SPTLC3, but not SPTLC1 or SPTLC2, is a key factor in high-FAT-diet-induced metabolic diseases. We have three specific aims. Aim 1: to characterize age- and high-FAT-diet-induced expression of SPTLC3. Aim 2: to determine the effect of SPTLC3 deficiency on high-FAT-diet-promoted insulin resistance and obesity in aged mice. Aim 3: to determine the impact of SPTLC3 KO and overexpression on high-FAT-diet-induced fatty liver, dyslipidemia, and atherosclerosis in aged mice. Our results will indicate whether inhibiting SPT by targeting SPTLC3 could prevent and/or treat MAFLD, insulin resistance, dyslipidemia, and atherosclerosis in aged humans.