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srebp-2

Properties1
aliasesSREBP-2, SREBF2, sterol regulatory element-binding protein 2, SREBP2

18 min read

SREBP-2 (SREBF2)

SREBP-2 (Sterol Regulatory Element-Binding Protein 2) is the master transcriptional regulator of hepatic cholesterol homeostasis. It controls expression of the LDL receptor (ldlr), the full cholesterol biosynthesis gene program (hmgcr and >20 downstream enzymes), and — paradoxically — pcsk9, the protein that degrades the LDL receptor. The SCAP–INSIG–SREBP-2 sterol-sensing axis is the molecular mechanism by which dietary saturated fat suppresses hepatic LDLR expression and thereby raises plasma LDL/ApoB.

Identity

  • UniProt: Q12772 (SRBP2_HUMAN), reviewed Swiss-Prot entry
  • Gene: SREBF2 (Sterol Regulatory Element Binding Transcription Factor 2)
  • NCBI Gene ID: 6721
  • HGNC: 11290
  • Ensembl: ENSG00000198911
  • Length: 1,141 amino acids (precursor); processed nuclear form ~520 aa
  • Mouse ortholog: Srebf2 (one-to-one ortholog; mechanism conserved in all mammalian species studied)

SREBP family context

Three SREBP isoforms exist in humans, encoded by two genes 1:

IsoformGenePrimary target programKey activator
SREBP-1aSREBF1 (long promoter)Both cholesterol and fatty acid synthesisBroad transcriptional activator
SREBP-1cSREBF1 (short promoter)Fatty acid and triglyceride synthesisInsulin, LXR
SREBP-2SREBF2Cholesterol synthesis and uptakeSterol depletion

SREBP-2 is the cholesterol-specific isoform and the primary regulator of ldlr expression. SREBP-1c is the lipogenic isoform predominantly induced by insulin via the insulin-igf1 pathway and by liver X receptor (LXR) agonists. All three isoforms share the same proteolytic activation mechanism, but differ in target-gene selectivity based on their transcriptional activation domain composition.

Domain architecture

The 1,141-aa precursor contains three functional regions 2 1:

  • N-terminal transcriptional activation domain + bHLH-LZ domain (residues ~1–480): Contains an acidic transcriptional activation domain (residues 1–50) and a basic helix-loop-helix leucine zipper (bHLH-LZ, bHLH at ~330–380, LZ at ~380–401) that mediates DNA binding to sterol regulatory elements (SRE-1 motif: 5’-ATCACCCCAC-3’) and E-boxes, and homo/heterodimerization. This N-terminal fragment is the active nuclear transcription factor released by proteolytic cleavage.
  • Two transmembrane spans (~480–580): Anchor the precursor in the ER membrane in a hairpin loop topology. S2P (MBTPS2) cleaves within the first transmembrane span at approximately Leu-484 (based on tryptic peptide mapping from HeLa nuclear extracts; Duncan et al. 1997, J Biol Chem 272:12778). The luminal loop between the two TM spans is the site of S1P (MBTPS1) cleavage between a Leu-Ser bond in the sequence RSVL↓S, corresponding to approximately Leu-522 in human SREBP-2 (Duncan et al. 1997); the adjacent positively-charged residue at P4 (equivalent to Arg) is required for S1P recognition 2.
  • C-terminal regulatory domain (residues ~580–1,141): Interacts with SCAP (SREBP cleavage-activating protein) via a MELADL hexapeptide motif; this interaction is essential for trafficking of the SCAP–SREBP-2 complex from ER to Golgi. INSIG proteins compete with SCAP for binding in this region when cholesterol is abundant.

Key PTMs (UniProt Q12772): phosphorylation at Ser-855 and Ser-1098 (regulatory); ubiquitination of the nuclear form (promoting degradation); SUMOylation at Lys-464 (modulates transcriptional activity); proteolytic cleavage by MBTPS1 (Leu-Ser bond, ~Leu-522 in lumenal loop), MBTPS2 (~Leu-484 within first TM span), and caspase-3/7.

The SCAP–INSIG–S1P/S2P sterol-sensing mechanism

This is the central regulatory axis. It operates as a cholesterol-sensing rheostat in the ER membrane 2 3.

Step-by-step:

  1. Ground state (cholesterol replete): Inactive SREBP-2 precursor sits in the ER membrane bound to SCAP (SREBP cleavage-activating protein, encoded by SCAP). When the ER membrane free-cholesterol concentration is high (>5 mol% of total ER lipid), SCAP undergoes a conformational change that exposes its MELADL hexapeptide motif. INSIG-1 or INSIG-2 (ER-resident proteins) then bind this motif, physically retaining the SCAP–SREBP-2 complex in the ER.
  2. Activation trigger (cholesterol depleted): When cellular free cholesterol falls — through statin inhibition of HMGCR, low dietary cholesterol intake, or increased PUFA-driven β-oxidation diverting acetyl-CoA away from synthesis — SCAP’s sterol-sensing domain loses its cholesterol ligand, INSIG dissociates, and the SCAP–SREBP-2 complex is loaded into COPII vesicles for anterograde transport to the Golgi.
  3. S1P cleavage (Golgi): Site-1 Protease (MBTPS1, a membrane-anchored serine protease) cleaves SREBP-2 in the luminal loop at a Leu-Ser bond (sequence RSVL↓S; cleavage requires a positively charged residue — Arg or Lys — at the P4 position) 2. This releases the C-terminal regulatory domain still bound to SCAP, leaving the N-terminal bHLH-LZ domain tethered to a single transmembrane span.
  4. S2P cleavage (Golgi): Site-2 Protease (MBTPS2, a zinc metalloprotease) then cleaves within the first transmembrane span (approximately Leu-484 based on fragment sizing; the exact bond is within a DRSR-preceded tetrapeptide), releasing the soluble N-terminal bHLH-LZ fragment (~480 aa).
  5. Nuclear translocation: The released fragment translocates to the nucleus, dimerizes, and binds SRE-1 elements in target gene promoters to activate transcription 4.

This two-protease sequential mechanism (first established by Brown & Goldstein 1997) is required; S2P cannot cleave unless S1P has acted first. The sterol signal is sensed in the ER; the proteolytic machinery is in the Golgi; the output is transcriptional.

Target genes

SREBP-2 binds SRE-1 elements to directly activate 1:

Cholesterol uptake:

  • LDLR — the LDL receptor; primary determinant of plasma LDL/ApoB clearance rate needs-replication (individual contribution of SREBP-2 vs other TFs at LDLR promoter is well-established but complex)
  • PCSK9 — (see feedback paradox below; established as SREBP-2 target by Dubuc 2004 and Jeong 2008 — not in Horton 2002, which predates PCSK9 discovery 5 6)

Cholesterol biosynthesis (full mevalonate pathway):

  • HMGCR — HMG-CoA reductase (rate-limiting enzyme; statin target)
  • HMGCS1 — HMG-CoA synthase 1
  • MVK — mevalonate kinase
  • PMVK — phosphomevalonate kinase
  • MVD — mevalonate diphosphate decarboxylase
  • FDPS — farnesyl diphosphate synthase
  • FDFT1 — squalene synthase
  • SQLE — squalene epoxidase
  • LSS — lanosterol synthase
  • DHCR24 — 24-dehydrocholesterol reductase
  • DHCR7 — 7-dehydrocholesterol reductase

The PCSK9 feedback paradox: SREBP-2 activates PCSK9 transcription via an SRE in the PCSK9 promoter 5 6. PCSK9 then promotes lysosomal degradation of the LDL receptor. This creates a built-in negative feedback brake on LDLR upregulation: as SREBP-2 is activated, it simultaneously induces PCSK9, which partially offsets the LDLR induction. Statins exploit this pathway (they activate SREBP-2 → ↑LDLR) but also co-induce PCSK9, which limits the statin-induced LDLR response. PCSK9 inhibitors bypass this brake by stabilizing LDLR post-translationally 6. See pcsk9.

Dietary fat regulation — the dietary fat → LDL/ApoB mechanism

This is the molecular basis for the dietary saturated fat → LDL/ApoB → CVD relationship 7.

Saturated fat (palmitate) raises plasma LDL/ApoB via SREBP-2 suppression:

  1. Dietary saturated fatty acids (especially palmitic acid, C16:0, and stearic acid, C18:0) are converted in the liver to saturated cholesterol esters and modulate the free-cholesterol pool in the ER membrane.
  2. Elevated hepatocyte free cholesterol → INSIG-mediated SCAP retention in ER → ↓ SCAP–SREBP-2 trafficking to Golgi → ↓ MBTPS1/MBTPS2 cleavage → ↓ nuclear SREBP-2 → ↓ LDLR transcription.
  3. ↓ Surface LDLR → ↓ hepatic LDL clearance → ↑ plasma LDL-cholesterol and ↑ ApoB.

The Mensink 2003 meta-analysis of 60 metabolic-ward feeding trials is the human evidence base confirming that saturated fat raises LDL and total:HDL ratio relative to unsaturated fat and carbohydrate 7.

PUFA opposes saturated fat via depletion of the ER free-cholesterol pool:

Polyunsaturated fatty acids (linoleic acid n-6; alpha-linolenic acid n-3; EPA/DHA) are preferentially oxidized in mitochondria and peroxisomes, diverting acetyl-CoA away from de novo cholesterol synthesis, and may also directly influence ER membrane cholesterol composition. Net effect: ↓ ER free-cholesterol → INSIG releases SCAP → ↑ SREBP-2 cleavage → ↑ LDLR → ↑ LDL clearance → ↓ plasma LDL/ApoB. This mechanism provides a partial mechanistic explanation for the LDL-lowering effect of replacing saturated with unsaturated fat.

DimensionStatus
Pathway conserved in humans?yes
Phenotype conserved in humans?yes — plasma LDL changes with dietary fat composition are well-documented in humans
Replicated in humans?yes — metabolic-ward RCTs (Mensink 2003 meta-analysis of 60 trials)

Pharmacological exploitation of the SREBP-2 axis

Three drug classes work through or around SREBP-2 1 6:

1. Statins — exploit SREBP-2 feedback Statins inhibit HMGCR → deplete hepatic free-cholesterol pool → activate SCAP–SREBP-2 trafficking → ↑ nuclear SREBP-2 → ↑ LDLR transcription (~2–3 fold) → ↑ hepatic LDL uptake. The LDL-lowering effect of statins is primarily mediated through LDLR upregulation, not through the modest direct reduction in de novo cholesterol synthesis 1. The co-induction of PCSK9 partially limits this response.

2. PCSK9 inhibitors — bypass the SREBP-2/PCSK9 brake Monoclonal antibodies (evolocumab, alirocumab) prevent PCSK9 from binding the LDLR in endosomes, allowing receptor recycling back to the hepatocyte surface. PCSK9i action is entirely post-translational and independent of SREBP-2 activation state. This is why PCSK9i + statins are additive: statins upregulate LDLR transcription (SREBP-2-dependent); PCSK9i stabilize the resulting protein (SREBP-2-independent). See pcsk9.

3. Bempedoic acid — acts upstream of SREBP-2 Bempedoic acid inhibits ATP-citrate lyase (ACLY) → reduces cytosolic acetyl-CoA → reduces de novo cholesterol/fatty acid synthesis → depletes hepatic cholesterol pool → activates SREBP-2 → ↑ LDLR 8. The mechanism is analogous to statins but targets a step upstream of HMGCR. Notably, bempedoic acid requires hepatic activation (by ACSL1) and does not inhibit ACLY in skeletal muscle, explaining its lower myopathy risk compared to statins.

Druggability rationale (tier 2): No FDA-approved drug directly targets SREBP-2 itself (no clinical SREBP-2 inhibitor or activator exists). However, the axis is highly druggable indirectly: statins (FDA-approved, widespread), bempedoic acid (FDA-approved 2020), and PCSK9i (FDA-approved) all modulate the physiological output (LDLR expression and LDL clearance) by engaging upstream or downstream steps. Research-stage direct SREBP inhibitors include betulin (natural triterpenoid, preclinical only) and fatostatin (blocks SCAP–SREBP-2 interaction, preclinical only) — neither has entered clinical trials.

Cross-talk with aging-relevant pathways

mTORC1 promotes SREBP-2 maturation

mTORC1 (mechanistic target of rapamycin complex 1 — see mtor) phosphorylates lipin-1 to retain it in the cytoplasm. When lipin-1 is dephosphorylated and enters the nucleus (mTORC1 OFF state), it suppresses SREBP transcriptional activity and reduces nuclear SREBP protein abundance. mTORC1 inactivates lipin-1 nuclear entry → relieves lipin-1-mediated SREBP suppression → ↑ SREBP-2 nuclear activity 9. The molecular mechanism by which nuclear lipin-1 reduces nuclear SREBP protein is not fully characterized in Peterson 2011 (no direct lipin-1–SREBP-2 physical interaction was detected), but the catalytic phosphatase activity of lipin-1 and its effect on nuclear lamina structure are implicated. Rapamycin treatment therefore reduces SREBP-2 target gene expression and cholesterol synthesis in a lipin-1-dependent manner. This explains, in part, why rapamycin-treated animals show reduced plasma cholesterol and why the mTOR pathway is considered pro-anabolic for sterol metabolism. The mTOR-SREBP-2 link connects deregulated-nutrient-sensing directly to age-related dyslipidemia.

Aging implication: Age-associated mTORC1 hyperactivation (documented in liver among other tissues) is expected to maintain inappropriately elevated SREBP-2 activity even when cellular cholesterol is sufficient — potentially contributing to excess cholesterol synthesis and PCSK9 induction in aged hepatocytes. Yang 2024 (cynomolgus monkey single-nucleus liver atlas, Protein & Cell) provides direct empirical support for this prediction 10: SREBP signaling is hyperactivated in aged primate hepatocytes across all three liver zonations, and forced SREBP2 activation in human primary hepatocytes is sufficient to recapitulate aging phenotypes (impaired detoxification, accelerated cellular senescence). The Yang finding promotes the mTORC1-driven hyperactivation prediction from a mechanistic inference to an empirically-anchored claim — although mTORC1 dependency per se is not yet directly tested in aged primate liver. Critically, this reverses the field-shorthand “reduced SREBP-2 processing efficiency” that had been used to explain age-related hepatic LDLR decline (e.g., on lipoprotein-metabolism); the mechanism is more accurately framed as SREBP-2 hyperactivation with the co-induced PCSK9 feedback brake dominating over LDLR transcriptional drive (see ldlr § Aging relevance).

AMPK opposes SREBP-2 via direct phosphorylation

AMPK directly phosphorylates both SREBP-1c and SREBP-2, inhibiting their cleavage and suppressing nuclear translocation — reducing LDLR and HMGCR transcription 11. For SREBP-1c, the characterized AMPK phosphorylation site is Ser-372 (required for AMPK-dependent inhibition of proteolytic processing; mutation S372A abolishes AMPK-mediated suppression). SREBP-2 is also a direct AMPK substrate (shown by in vitro kinase assay with recombinant AMPK and GST-SREBP-2) but the equivalent conserved site on SREBP-2 is not explicitly numbered in Li 2011; it is likely the conserved serine in the equivalent N-terminal position given the shared substrate motif 11. This places SREBP-2 downstream of the cellular energy sensor ampk (activated by ↑AMP:ATP ratio, metformin, caloric restriction). AMPK activation thus reduces both cholesterol biosynthesis and LDLR expression; the net metabolic effect is a shift away from anabolic lipid synthesis under energy stress.

Importantly, AMPK activation also inhibits HMGCR (the statin target) via direct phosphorylation of a distinct site — so AMPK suppresses cholesterol synthesis via two mechanisms simultaneously: (1) SREBP-2 phosphorylation → ↓ LDLR/HMGCR transcription; (2) HMGCR direct phosphorylation → ↓ enzymatic activity.

Insulin/LXR and SREBP-1c cross-talk

Insulin (via insulin-igf1 → PI3K/AKT → SREBP-1c promoter activation via LXR) primarily drives SREBP-1c-mediated fatty acid synthesis, not SREBP-2. However, high-insulin states (as in insulin resistance/obesity) indirectly promote SREBP-2 activity by: (1) mTORC1 hyperactivation → lipin-1 suppression (above); (2) increased hepatic lipid accumulation → ER stress → SCAP–INSIG regulatory perturbation. no-mechanism — the specific ER-stress–INSIG connection is incompletely characterized.

Aging relevance

SREBP-2 occupies a central node in the deregulated-nutrient-sensing hallmark. The current best-supported model (post Yang 2024 single-nucleus primate liver atlas, yang-2023-primate-liver-aging-snrna-srebp2) is:

  1. SREBP-2 hyperactivation per hepatocyte with age — Yang 2024 snRNA-seq of cynomolgus liver across three zonations shows hyperactivated SREBP signaling as a defining feature of the aged hepatocyte transcriptome; forced SREBP2 activation in human primary hepatocytes is sufficient to recapitulate aging phenotypes (impaired detoxification, accelerated senescence) 10. This is consistent with the mTORC1 → lipin-1 → SREBP-2 axis (mtor; Peterson 2011) operating in aged liver, though the mTORC1 dependency has not been directly tested in primate-aged tissue (e.g., via rapamycin arm) — see Limitations below.
  2. PCSK9-feedback dominance over LDLR transcriptional drive — because pcsk9 is co-induced by SREBP-2 (Dubuc 2004, Jeong 2008; SRE in the PCSK9 promoter), SREBP-2 hyperactivation drives both LDLR and PCSK9 transcripts up. The protein-level outcome depends on which arm dominates. Plasma PCSK9 protein has been reported to rise with age (Cui 2010 Chinese cohort n=479; Lakoski 2009 Dallas Heart Study n=3138 — pre-2015 anchors; no 2019+ replication in age-stratified healthy cohorts), and the empirically-observed phenotype is net LDLR surface-density decline → reduced plasma LDL clearance → cumulative LDL exposure rises (the Ference 2024 LDL-years framework on apob).
  3. Bulk vs single-cell discordance — methodological caveat. GTEx v10 bulk RNA-seq of human liver shows SREBF2 transcript with weak negative trend (Spearman ρ ≈ −0.07, n=262 donors aged 20–79; this wiki, 2026-05-21 query). The discordance with Yang’s snRNA-seq hyperactivation is consistent with the canonical cell-composition confound: aged liver has reduced hepatocyte fraction (more immune infiltrate, stellate-cell activation, fibrosis), so per-hepatocyte increases can be diluted out of bulk-tissue measurements. Single-nucleus data is the right instrument for this question; bulk RNA-seq is the wrong instrument.

The pathway also intersects chronic-inflammation: NLRP3 inflammasome activation (upstream of IL-1β release, a driver of chronic-inflammation) has been reported to be promoted by SREBP-2 in macrophages within atherosclerotic lesions — distinct from the hepatic LDLR-regulation role 12. Yang 2024 also reports upregulation of chronic-inflammation–related genes alongside SREBP signaling in aged hepatocytes, suggesting the inflammation–SREBP-2 link may be bidirectional in aging.

The pathway also intersects chronic-inflammation: NLRP3 inflammasome activation (upstream of IL-1β release, a driver of chronic-inflammation) has been reported to be promoted by SREBP-2 in macrophages within atherosclerotic lesions — distinct from the hepatic LDLR-regulation role 12. Whether this represents an aging-amplifying loop is speculative.

Limitations and gaps

  • ✅ gtex-aging-correlation: populated 2026-05-21 — direct GTEx v10 API query (attributeSubset=ageBracket parameter on /expression/geneExpression) returned per-age-bracket arrays for SREBF2 across multiple tissues. Hepatic SREBF2 ρ = −0.07 (n=262, not significant); pan-tissue weak/null pattern. The bulk-tissue signal does not match the single-nucleus signal from Yang 2024 (per-hepatocyte SREBP signaling hyperactivated) — cell-composition confound favors the snRNA result as the true per-hepatocyte direction. See sops/finding-tissue-expression.md (updated 2026-05-21) for the attributeSubset=ageBracket workflow.
  • ⚠️ Partially resolved (Yang 2024) — direct demonstration that age-associated SREBP-2 hyperactivation occurs in primate liver is now published (Yang et al. 2024, yang-2023-primate-liver-aging-snrna-srebp2). What remains untested: (a) mTORC1 dependency of the SREBP-2 hyperactivation phenotype in aged primate liver (no rapamycin arm); (b) replication in aged human liver biopsies/autopsy — Yang’s human work is in primary hepatocytes with forced SREBP2 activation, not aged human tissue.
  • #gap/no-mechanism — The specific mechanism by which ER stress perturbs INSIG function and thereby dysregulates SREBP-2 in the context of hepatic steatosis is incompletely characterized.
  • #gap/needs-human-replication — AMPK-mediated direct phosphorylation of SREBP-2 (and SREBP-1c Ser-372) was demonstrated in diet-induced insulin-resistant LDLR-deficient mice and in HepG2 cells; the equivalent in vivo human liver data is limited.
  • #gap/not-populated — mr-causal-evidence: not-tested reflects that SREBF2 is not a standard Mendelian randomization instrument target: most MR work for LDL/ApoB uses genome-wide polygenic instruments or LDLR/PCSK9 variants rather than SREBF2 variants. GWAS hits at the SREBF2 locus may exist; an instrument-availability check against the GWAS Catalog has not been done for this page. Populate per sops/finding-population-evidence.md.
  • #gap/needs-canonical-id — GenAge status of SREBF2 was not confirmed via direct API query; a manual lookup at genomics.senescence.info/genes is needed. If listed, populate genage-id:.

Cross-references

  • ldlr — primary SREBP-2 target gene; expression driven by SREBP-2 cleavage
  • hmgcr — rate-limiting cholesterol synthesis enzyme; SREBP-2 transcriptional target and statin target
  • pcsk9 — co-induced by SREBP-2; degrades LDLR; feedback brake on LDLR upregulation
  • apob — the LDL particle protein; plasma ApoB is the downstream readout of LDLR-mediated clearance
  • atherosclerosis — disease consequence of impaired LDLR-mediated LDL clearance
  • mtor — mTORC1 phosphorylates lipin-1 to promote SREBP-2 activity
  • ampk — directly phosphorylates SREBP-2 (and SREBP-1c at Ser-372) to suppress cleavage and nuclear translocation
  • deregulated-nutrient-sensing — hallmark in which the mTOR–SREBP-2 axis is embedded
  • chronic-inflammation — downstream consequence; SREBP-2 → PCSK9 excess → ↑ LDL → atherosclerotic plaque → IL-1β/inflammasome
  • insulin-igf1 — insulin activates SREBP-1c via LXR; cross-talk with SREBP-2 under insulin resistance
  • familial-hypercholesterolemia — when LDLR is genetically defective, the SREBP-2 → LDLR feedback can’t compensate; statins still partially work via residual LDLR upregulation
  • lipoprotein-metabolism — integrated pathway view; SREBP-2 sets the LDLR ceiling for the endogenous-clearance arm

Footnotes

Footnotes

  1. doi:10.1172/JCI15593 · Horton JD, Goldstein JL, Brown MS · J Clin Invest 2002 · review · n=not-applicable · model: human + mouse · comprehensive review of SREBP isoform biology, target genes, and pharmacological implications; 4301 citations; archive status: pending download ↩ ↩2 ↩3 ↩4 ↩5

  2. doi:10.1016/s0092-8674(00)80213-5 · Brown MS, Goldstein JL · Cell 1997 · review · n=not-applicable · model: human cell lines + in-vivo mouse · landmark review establishing the SCAP-mediated proteolytic activation mechanism of SREBPs; local PDF confirmed in archive ↩ ↩2 ↩3 ↩4

  3. doi:10.1146/annurev-biochem-062917-011852 · Brown MS, Radhakrishnan A, Goldstein JL · Annu Rev Biochem 2018 · review · n=not-applicable · definitive retrospective on SCAP’s central role in sterol sensing including the MELADL hexapeptide mechanism; 457 citations; archive status: pending download ↩

  4. doi:10.1073/pnas.96.20.11041 · Brown MS, Goldstein JL · PNAS 1999 · review · n=not-applicable · mechanistic overview of the two-protease S1P/S2P pathway; 1317 citations; archive status: not_oa ↩

  5. doi:10.1194/jlr.M700443-JLR200 · Jeong HJ, Lee HS, Kim KS et al. · J Lipid Res 2008 · in-vitro (HepG2, mouse hepatocytes) · sterol-dependent regulation of PCSK9 promoter via SRE requires SREBP-2; 345 citations; archive status: pending download ↩ ↩2

  6. doi:10.1161/01.ATV.0000134621.14315.43 · Dubuc G, Chamberland A, Wassef H et al. · Arterioscler Thromb Vasc Biol 2004 · in-vitro + human pharmacology · statins upregulate PCSK9 via SREBP-2-mediated SRE activation; foundational paper establishing the PCSK9–statin paradox; 598 citations; archive status: not_oa ↩ ↩2 ↩3 ↩4

  7. doi:10.1093/ajcn/77.5.1146 · Mensink RP, Zock PL, Kester AD, Katan MB · Am J Clin Nutr 2003 · meta-analysis of 60 controlled trials · n=~1000+ subjects across trials · quantifies effects of individual dietary fatty acids and carbohydrates on serum lipids and apolipoproteins; 2767 citations; archive status: pending download ↩ ↩2

  8. doi:10.1016/j.arteri.2021.02.012 · Masana Marín L, Plana Gil N · Clin Investig Arterioscler 2021 · review · bempedoic acid mechanism: ACLY inhibition → ↓ acetyl-CoA → ↓ cholesterol synthesis → SREBP-2 activation → ↑ LDLR; archive status: pending download ↩

  9. doi:10.1016/j.cell.2011.06.034 · Peterson TR, Sengupta SS, Harris TE et al. · Cell 2011 · in-vitro + mouse · mTORC1 phosphorylates and excludes lipin-1 from nucleus, relieving SREBP suppression; rapamycin reverses this; 1170 citations; archive status: pending download ↩

  10. yang-2023-primate-liver-aging-snrna-srebp2 · doi:10.1093/procel/pwad039 · PMID 37378670 · PMC10833472 · Yang S, Liu C,… Liu GH (Aging Biomarker Consortium) · Protein & Cell 2024;15(2):98-120 · in-vivo single-nucleus RNA-seq (cynomolgus monkey liver, multi-age cohort) + in-vitro mechanistic validation (human primary hepatocytes with forced SREBP2 activation) · SREBP signaling hyperactivated as a hallmark of the aged primate liver across all three hepatocyte zonations; forced SREBP2 activation in human primary hepatocytes is sufficient to recapitulate aging phenotypes (impaired detoxification + accelerated cellular senescence) · Gold OA via OUP/PMC · ⚠️ abstract-verified 2026-05-21; full PDF read pending — study page is verified: false ↩ ↩2

  11. doi:10.1016/j.cmet.2011.03.009 · Li Y, Xu S, Mihaylova MM et al. · Cell Metabolism 2011 · in-vivo (diet-induced insulin-resistant mice) + in-vitro · AMPK phosphorylates SREBP at Ser-372; inhibits nuclear translocation; reduces hepatic lipogenesis and atherosclerosis; 1692 citations; archive status: pending download ↩ ↩2

  12. doi:10.1371/journal.pone.0067532 · Li Y, Xu S, Jiang B et al. · PLoS One 2013 · in-vivo (atherosclerotic diabetic pigs) · SREBP and NLRP3 inflammasome co-activation in atherosclerotic lesions; archive status: not confirmed in archive ↩ ↩2

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