{"doi":"10.1002/ctm2.1147","title":"Intracellular lipid surveillance: Modulating protein dynamics through lipid sensing","abstract":"Lipids play fundamental roles in nearly all biological processes. While this class of macromolecules is expansive and complex, lipid roles in the cell can be confined to three major functions: membrane composition, signalling and energetic reserve. In cellular and organellular membranes, lipids provide structural integrity, compositional specificity and compartmentalisation. In the maintenance of cellular and metabolic homeostasis, lipid-derived hormones serve as regulatory ligands in signal transduction pathways that promote growth and development.1 The sterol lipid, cholesterol, serves as both an important membrane component and the precursor for most steroid hormones.2 Noteworthy discoveries involving the regulation of lipids include the identification and characterisation of cholesterol sensing through the sterol regulatory element binding protein (SREBP), which couples sterol availability with membrane composition and steroidogenesis.3 When cholesterol availability is limited, SREBP promotes lipogenesis to increase sterol production and restore membrane fluidity. This seminal discovery initiated our understanding of sterol lipid sensing and represented the first molecular mechanism for regulating lipid availability. However, how cells measure their lipid availability in the context of maintaining energetic reserves remains an important yet outstanding question. Specifically, it was unclear how a starving cell detects and responds to the depletion of its intracellular lipid pools. Similar to lipid storage in adipose tissue, nearly every cell in the body stores lipids in the form of lipid droplets. These lipid reservoirs provide cells an intrinsic source of carbon-rich molecules that can be rapidly utilised as substrates for mitochondrial respiration and downstream energy production, in the form of adenosine triphosphate (ATP), upon metabolic demand.4 Energy released from ATP hydrolysis is essential for nearly every biological process and therefore requires tight regulation to ensure cellular survival. Since cells continuously metabolise their lipid stores for energy production, they must simultaneously replenish metabolic resources through nutrient absorption. When extracellular resources become limited, as with reduced systemic nutrient availability or in tissues with limited blood flow, cells must be able to detect lipid depletion and initiate a response to both increase nutrient intake and restore metabolic homeostasis. While such mechanisms had not previously been described, a recent study published in Nature defined a novel intracellular lipid surveillance pathway that allows intestinal cells in the roundworm, Caenorhabditis elegans, to sense and respond to lipid depletion.5 Watterson et al. implicated a single de novo-synthesised lipid, geranylgeranyl pyrophosphate (GGPP), as a cellular indicator of total lipid availability through its ability to sequester and inactivate the starvation-activated transcriptional regulator, nuclear hormone receptor 49 (NHR-49),6 in the cytosol.5 This study demonstrates that under conditions of ample resources, NHR-49, the C. elegans orthologue of mammalian nuclear receptors, hepatic nuclear factor 4 and peroxisome proliferator-activated receptor, is retained in the cytosol in an inactive state through its physical association with endocytic transport vesicles. To remain associated with the vesicle, NHR-49 requires the prenol lipid, GGPP, and its conjugation to the small G protein, RAB-11.1. Synthesis of GGPP via the mevalonate/isoprenoid pathway requires intracellular carbon resources such as those heavily represented in lipid droplets, which are ultimately metabolised to acetyl-coenzyme A , the two-carbon precursor for this biosynthetic pathway7 (Figure 1). When intracellular lipids become limited, cells lack the appropriate carbon-rich resources needed to synthesise GGPP, thereby preventing NHR-49 vesicular retention and allowing for its translocation into the nucleus. Once nuclear, ","journal":"Clinical and Translational Medicine","year":2022,"id":285858,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":419858,"name":"Peter M. Douglas","orcid":"0000-0002-0734-1049","position":1,"is_corresponding":false},{"id":879857,"name":"Abigail Watterson","orcid":"0000-0002-5204-0907","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T00:29:48.841035Z","pmid":"36536483","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}