How is transcriptional regulation of lipogenesis linked to diet and environment
in C. elegans and mammals
SREBP (sterol regulatory element binding protein) transcription factors activate
genes important for cholesterol metabolism, fatty acid (FA) and synthesis of
phospholipids, in addition to ensuring production of additional important co-factors.
We have found unexplored regulatory links between lipid metabolism and the one-carbon
cycle (1CC), discovering that SREBP proteins in C. elegans and mammals
control expression of 1CC genes. The 1CC provides methyl groups for PL biosynthesis
and epigenetic regulation; regulation by SREBPs provides a novel layer of nutrition-dependent
input to methylation-dependent processes. Alterations in 1C metabolism and SREBP
function are associated with similar diseases, suggesting that co-regulation
with lipid homeostasis may be a common impact point in metabolic-associated
disorders such as obesity and fatty liver disease.
Most methylation reactions require SAMe (s-adenosyl methionine). Conversion
of methionine to SAMe by MAT1A/MAT2A in humans, or the SAMS proteins in C.
elegans, affects cellular processes from phosphatidylcholine (PC) biosynthesis
to protein or DNA modification. We have found that SREBPs regulate sams-1
and MAT1A expression in both C. elegans and human cells. In C.
elegans, sams-1 decrease or loss causes lipid accumulation reminiscent of
hepatic steatosis occuring in MAT1A KO mice (Lu et al. PNAS 2001), suggesting
models for lipid accumulation in sams-1 animals may be relevant to hepatic
steatosis in mammals. Because the 1CC is implicated in multiple fatty liver
models and metabolites such as folate or choline are administered as treatments
for disease, it is crucial to understand the connections between the 1CC and
We are interested in how lipid homeostasis is affected by genetic or dietary
changes in 1CC function and how SBP-1/SREBP affects cellular processes such
as epigenetic modification by regulating the supply of methyl donors. These
projects will include mechanistic studies in mammalian cell culture, in vivo
studies in mouse liver as well as genetics screens for discovery in C. elegans.
In our studies of SREBP regulation by SIRT1 (Walker, et al. 2010, Genes and
Development) and of SREBP regulation of the 1CC (Walker, A., Jacobs, R. et al.,
Cell, 2011), this combination of models has allowed us to rapidly establish
functional biological relationships between pathways in C. elegans, then
determine relevance to mammalian physiology and precise molecular mechanisms
in mouse knockout or human cell culture models. These types of experiments are
important for determining mechanistic relationships between metabolic pathways
and cellular function, and furthermore, will aid in our understanding about
how these pathways contribute to human disorders such as metabolic syndrome.
Figure. In C. elegans, SBP-1-Dependent
Lipogenesis and Gene Expression Are Increased after sams-1(RNAi)
(A) RNAi knockdown of sams-1 revealed large refractile droplets in the
intestine and body cavity by Nomarski optics.