Preventing Phosphorylation of Sterol Regulatory Element-Binding Protein 1a by MAP-Kinases Protects Mice from Fatty Liver and Visceral Obesity

Abstract

The transcription factor sterol regulatory element binding protein (SREBP)-1a plays a pivotal role in lipid metabolism. Using the SREBP-1a expressing human hepatoma cell line HepG2 we have shown previously that human SREBP-1a is phosphorylated at serine 117 by ERK-mitogen-activated protein kinases (MAPK). Using a combination of cell biology and protein chemistry approach we show that SREBP-1a is also target of other MAPK-families, i.e. c-JUN N-terminal protein kinases (JNK) or p38 stress activated MAP kinases. Serine 117 is also the major phosphorylation site in SREBP-1a for JNK. In contrast to that the major phosphorylation sites of p38 MAPK family are serine 63 and threonine 426. Functional analyses reveal that phosphorylation of SREBP-1a does not alter protein/DNA interaction. The identified phosphorylation sites are specific for both kinase families also in cellular context. To provide direct evidence that phosphorylation of SREBP-1a is a regulatory principle of biological and clinical relevance, we generated transgenic mice expressing mature transcriptionally active N-terminal domain of human SREBP–1a variant lacking all identified phosphorylaton sites designed as alb-SREBP-1aΔP and wild type SREBP-1a designed as alb-SREBP-1a liver specific under control of the albumin promoter and a liver specific enhancer. In contrast to alb-SREBP–1a mice the phosphorylation–deficient mice develop no enlarged fatty livers under normocaloric conditions. Phenotypical examination reveales a massive accumulation of adipose tissue in alb-SREBP-1a but not in the phosphorylation deficient alb-SREBP-1aΔP mice. Moreover, preventing phosphorylation of SREBP-1a protects mice also from dyslipidemia. In conclusion, phosphorylation of SREBP-1a by ERK, JNK and p38 MAPK-families resembles a biological principle and plays a significant role, in vivo.

Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling

“…However, the loss of Srebp-1 increases Srebp-2 expression and activity, compensating for the loss of Srebp-1 ( 59,60 ). Furthermore, while ( 58 ). Furthermore, JNK is required for optimal Srebp-1 activation and the subsequent increase in Scd-1 and Fasn in response to keratinocyte growth factor treatment ( 56 ).…”

A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes

“…It has been reported that insulin enhances the processing of pre-SREBP-1c in rat hepatocytes by promoting its phosphorylation and association with coatomer protein II vesicles where two sequential cleavages generate the n-SREBP-1c ( 53 ). A recent study showed that SREBP-1a is phosphorylated by extracellular signal-regulated kinase, JNK, and p38 mitogen-activated protein kinases, and preventing phosphorylation of SREBP-1a protects mice from fatty liver and visceral obesity ( 54 ). The insulin/JNK2 pathway may directly stimulate SREBP-1a or SREBP-1c activity, induce SREBP-1c expression, and may be involved in obesity-related disorders.…”

Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake

“…The events regulating the transcriptional expression of SREBP-2 , and the posttranslational modifi cations affecting SREBP-2 activity are well documented (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). On the other hand, microRNA (miR)-dependent SREBP-2 posttranscriptional regulation is only now being explored.…”