Regulation of Lipid Metabolism by Sterol Regulatory Element-Binding Proteins

Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that coordinate the synthesis of cholesterol, fatty acids and triglycerides by activating a network of lipogenic and cholesterogenic genes. Three major isoforms exist: SREBP-1a, SREBP-1c and SREBP-2, each displaying distinct promoter specificities derived from alternative transcription start sites. In the endoplasmic reticulum, SREBPs associate with SREBP cleavage-activating protein (SCAP) and are retained by insulin-induced gene (Insig) proteins under conditions of lipid sufficiency. Upon depletion of sterols or activation of upstream kinases such as mTORC1, SCAP escorts SREBPs to the Golgi for proteolytic release of the active nuclear forms, which then enter the nucleus to bind sterol regulatory elements (SREs). This proteolytic switch is finely tuned by energy-sensing kinases, nutrient availability and mechanical cues from the extracellular matrix, ensuring that de novo lipogenesis and cholesterol biosynthesis respond appropriately to physiological demands. Dysregulation of SREBP activity underlies hepatic steatosis, cardiovascular disease and features of metabolic syndrome, driving interest in pharmacological approaches that target proteolytic activation, Insig stability or upstream kinases to restore lipid homeostasis in metabolic disorders.

Research from Nature Portfolio

Recent studies have identified SPRING as a post-transcriptional modulator essential for hepatic SREBP activation. Liver-specific deletion of SPRING attenuates SREBP-mediated transcription, reduces plasma cholesterol across lipoprotein classes and confers protection against diet-induced hepatosteatosis, highlighting SPRING as a potential therapeutic entry point in hypercholesterolaemia. Work on mechanical regulation has revealed that extracellular matrix stiffness and geranylgeranyl pyrophosphate-dependent acto-myosin contractility converge on AMP-activated protein kinase (AMPK) to inhibit SREBP-1 activation; this mechano-metabolic axis influences stem cell fate and fat storage across species. Complementary findings show that AMPK phosphorylates Insig-1, stabilising the protein and preventing SREBP-1 cleavage and lipogenic gene expression in response to metformin, thereby attenuating hepatic lipid accumulation. Together, these advances delineate convergent pathways—post-translational regulators, mechanical cues and energy sensors—that refine SREBP activity in health and disease.

Regulation of Lipid Metabolism by Sterol Regulatory Element-Binding Proteins publication trend

The graph below shows the total number of articles in regulation of lipid metabolism by sterol regulatory element-binding proteins across all publications each year (not limited to Nature Index journals).

Technical terms

SREBP: Sterol regulatory element-binding protein, a family of transcription factors that govern lipid synthesis by binding sterol regulatory elements in gene promoters.

SCAP: SREBP cleavage-activating protein, an escort that senses sterol levels and mediates SREBP transport from the endoplasmic reticulum to the Golgi.

Insig: Insulin-induced gene proteins that retain SREBP–SCAP complexes in the endoplasmic reticulum under lipid-replete conditions.

De novo lipogenesis: The metabolic pathway converting acetyl-CoA into fatty acids and triglycerides, driven by enzymes induced by SREBPs.

mTORC1: Mechanistic target of rapamycin complex 1, a nutrient- and energy-sensing kinase complex that modulates SREBP activation in response to cellular status.

References

1. Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans. Nature Communications (2023).
2. Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism. Nature Communications (2019).
3. Post-translational regulation of lipogenesis via AMPK-dependent phosphorylation of insulin-induced gene. Nature Communications (2019).
4. Glycerol Kinase Drives Hepatic de novo Lipogenesis and Triglyceride Synthesis in Nonalcoholic Fatty Liver by Activating SREBP‐1c Transcription, Upregulating DGAT1/2 Expression, and Promoting Glycerol Metabolism. Advanced Science (2024).
5. ASGR1 deficiency diverts lipids toward adipose tissue but results in liver damage during obesity. Cardiovascular Diabetology (2024).
6. mTORC1 signaling in hepatic lipid metabolism. Protein & Cell (2017).