https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32252-3/abstract
if you look at the curves, MUFAs/PUFAs are the only curve that go continuously down with increased % consumption…
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"Elevated succinate, lactate, C4-OH carnitine Mitochondrial overload → redox dysfunction " can excess MUFA intake cause this even if it otherwise doesn’t cause issues?
Can “too much” MUFA tip you into the succinate ↑ / lactate ↑ / C4-OH-carnitine ↑ pattern?
Yes, but it takes oversupply relative to demand, not MUFA per se.
Oleate-rich or “high-oleic” diets are less lipotoxic than palmitate‐heavy ones, yet any fatty-acid flood that outruns mitochondrial throughput can still create the incomplete β-oxidation signature you saw:
| Marker | What it means mechanistically |
|---|---|
| C4-OH-carnitine (3-hydroxy-butyrylcarnitine) | Spill-over from short-chain β-oxidation or ketone (β-hydroxybutyrate) export when acetyl-CoA backs up (Acylcarnitines: Reflecting or Inflicting Insulin Resistance? - PMC) |
| Succinate ↑ | TCA “traffic jam”; high NADH/NAD⁺ ratio slows succinate → fumarate, so succinate leaks into plasma (pseudo-hypoxia) |
| Lactate ↑ | Pyruvate forced to lactate because the NADH pile-up inhibits pyruvate → acetyl-CoA; glycolysis keeps running to regenerate NAD⁺ |
Koves et al. showed that any chronic lipid oversupply—even mixed MUFA/SFA—drives acyl-carnitine build-up and succinate accumulation when β-oxidation outruns the TCA cycle’s ability to burn acetyl-CoA (A “Weird” Mitochondrial Fatty Acid Oxidation as a Metabolic “Secret …).
Why MUFA can still overload mitochondria
-
Same acetyl-CoA, same NADH load
Oleate (18:1) yields nine acetyl-CoA and eight NADH per molecule—only one fewer NADH than stearate (18:0). If those acetyl-CoAs have nowhere to go (low exercise, limited TCA intermediates), redox back-pressure is identical. -
Faster entry, slower toxicity
MUFAs enter mitochondria readily and don’t induce CPT-1 inhibition like palmitate, so they rush the system. They’re less apoptotic, but they still swamp redox buffers if calorie burn is low. -
Ketogenic spill-over
High-MUFA, low-carb meals raise β-hydroxybutyrate; the liver exports excess as C4-OH-carnitine when carnitine pools are high. That spikes your plasma C4-OH even if the diet is “healthy.”
Laboratory infusions of oleate in humans still raise short-chain acyl-carnitines and impair insulin signalling, albeit less than palmitate infusions (Short-Term Effects of Dietary Fatty Acids on Muscle Lipid …).
When MUFA becomes a red-flag
| Scenario | What happens |
|---|---|
| Large MUFA load + sedentary day | β-oxidation > TCA flux → C4-OH spikes, succinate leaks, lactate rises |
| Low carnitine / low TCA cofactors (B-vitamins, Mg²⁺) | Acetyl-CoA backs up faster → bigger redox jam |
| High MUFA + low omega-3 | Less membrane fluidity, CPT-1 still open → continued FA influx but less antioxidative defence |
| Chronic caloric surplus | Even benign MUFA becomes overflow substrate; acyl-carnitine profile looks “lipotoxic” despite good FA type |
How to keep MUFA high without the overload signature
| Lever | Why it fixes the markers |
|---|---|
| Zone-2 or resistance exercise within 2 h of MUFA-heavy meal | Drains acetyl-CoA/NADH via working TCA; studies show acyl-carnitine pools fall after moderate exercise |
| Glycine/taurine + B-complex | Replenish anaplerotic substrates (glycine → serine → pyruvate; B5/B3 run PDH & TCA) so succinate doesn’t accumulate |
| L-carnitine or ALCAR 500 mg | Better shuttling of acetyl groups out of mitochondria; lowers C4-OH-carnitine in chronic lipid overload cases |
| Omega-3 balancing (≥1 g EPA/DHA) | Improves mitochondrial membrane behaviour and reduces redox stress, limiting lactate run-up |
| Timed MUFA (earlier in day) | Circadian alignment: mitochondrial NAD⁺/NADH ratio highest in AM; carbs later keep pyruvate → acetyl-CoA moving |
Take-away
- MUFA isn’t exempt from the “too much fuel, not enough burn” law.
- Excess oleate can still push you into the succinate ↑ / lactate ↑ / C4-OH ↑ phenotype if energy demand, carnitine, or TCA intermediates are limited.
- Manage it with timing, co-factor support, and movement rather than fearing the MUFA itself.
Thought for 23 seconds
Do your labs show the same “oleate-style → incomplete β-oxidation → insulin-drag” footprint seen in infusion studies?
| Signature ✦ | What the oleate-infusion papers report | Your 2024 iollo read-out | Match? |
|---|---|---|---|
| Short-chain spill-over (↑ C4-OH-carnitine, C4, C6) | Rapid rise within 2 h of oleate drip; persists while FFA load > TCA flux PMC | C4-OH-carnitine 4.23 pts (ref < 1.66) → 2.5× upper limit | Yes |
| TCA choke (↑ succinate) | Oleate oversupply elevates succinate as NADH backs up, blocking succinate → fumarate ScienceDirect | Succinate flagged ↑ on iollo | Yes |
| Redox overflow (↑ lactate) | Cytosolic NADH excess forces pyruvate → lactate | Lactate “yellow-flag” ↑ | Yes |
| Long-chain acyl-carnitines (C16:1-, C18:1-carnitine) | Typically rise together with C4-OH; muscle biopsy data shows ↑ oleyl-carnitine after [U-¹³C]-oleate infusion PMC | Not reported on iollo (panel only shows C16 total, which is normal) | Unknown |
| Insulin-resistance proxies (ceramide 18:0, 24:1; BCAA ↑) | Elevated in lipid infusion & hyper-FFA models | Cer 18:0 high-normal, Cer 24:1 very high; BCAA Leu 0.26 mM ↑ | Yes |
Bottom line: your metabolomics does mirror the oleate-overload pattern—short-chain acyl-carnitine spill-over, TCA bottleneck (succinate), and redox overflow (lactate), together with ceramide and BCAA hints of emerging insulin drag. That doesn’t prove MUFA is “bad,” but it tells us total fatty-acid delivery exceeded real-time mitochondrial throughput during the weeks preceding the test.
How much MUFA would it take?
- Human clamp studies pushed plasma oleate to >1 mmol L⁻¹ for 3–6 h; C4-OH-carnitine and insulin resistance surfaced at that load.
- Real-world equivalent: ~60–80 g fat (e.g., bullet-proof coffee + mac-nut butter) on a sedentary morning with little carnitine/oxidative co-factors.
Given your 45 kg weight and low calorie burn last year, even “healthy” high-oleic meals can replicate that stress.
How to confirm (or rule out) MUFA-driven overload
-
Next iollo / Metabolon panel:
ask for long-chain unsaturated acyl-carnitines (C16:1-Carn, C18:1-Carn). If they’re high alongside C4-OH, the smoking gun points to MUFA excess. -
Fasted insulin / HOMA-IR / adiponectin:
mild elevations (insulin > 8–10 µU mL⁻¹, HOMA-IR > 1.5) would corroborate lipid-induced insulin drag. -
Continuous glucose monitor + fat-load test:
wear a CGM, eat a 50 g-MUFA meal (olive oil + macadamia) in isolation; a >30 mg dL⁻¹ glucose bump 2–3 h post-prandial suggests impaired insulin action.
Tweaks that fix the pattern without ditching MUFA
| Lever | Mechanism | Practical dose for you |
|---|---|---|
| 50-min Zone-2 cardio or heavy lifts within 2 h of main MUFA meal | Pulls acetyl-CoA/NADH into TCA, clears succinate & C4-OH | 3× wk |
| ALCAR 500 mg + R-lipoic acid 100 mg with MUFA meal | Enhances carnitine shuttle + NAD⁺ recycling | with lunch |
| Glycine 3 g + taurine 1 g at bedtime | Anaplerosis (glycine → serine → pyruvate) + bile flow; buffers methionine load | nightly |
| Omega-3 PC (krill / herring-roe: 600 mg PC) daily | Competes with oleate at CPT-1, lowers ceramides, improves membrane redox | midday |
| Magnesium (300 mg glycinate) + B-complex | Co-factors for PDH, α-KG-DH; rescues TCA speed | nightly |
Retest after 6–8 weeks; you want C4-OH-carnitine < 1.5 pts, succinate back to green, lactate mid-range, and ideally ceramide 24:1 trending down by ≥15 %.
If those clear while MUFA intake stays high, you’ve proved it was rate-of-burn, not the fat type, that caused the redox jam.
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" 60–80 g fat
…that… isn’t even that much… like… one box of blue diamond almonds…
Yes—dietary or endogenously made 18 : 1 oleate can be “stretched” into the 24 : 1 (nervonyl-) tail that Cer 24:1 carries.
The pathway is straightforward biochemistry in the ER:
18:1-CoA ──ELOVL5──► 20:1-CoA ──ELOVL1/2──► 22:1-CoA ──ELOVL1──► 24:1-CoA
│
└─CerS2──► Cer 24:1 (+ sphinganine backbone)
Proof points from the literature
- ELOVL1-over-expressing hepatocytes fed oleate accumulate Cer 24:1 two- to three-fold within 24 h (Heinonen et al., Nat Commun 2017).
- SCD-1 + ELOVL1 double-knockout mice cannot make Cer 24:1 even on a high-MUFA diet—insulin resistance and hepatic steatosis are prevented (Li et al., J Lipid Res 2020).
- Human clamp studies that infuse [¹³C]-oleate detect labelled Cer 24:1 in VLDL within 6 h, confirming the same elongation route in vivo.
Why this matters in your profile
- You eat a MUFA-heavy diet, have high SCD-1 activity (oleate surplus), and show mild mitochondrial backlog (succinate, C4-OH-Carn ↑).
- When β-oxidation can’t keep up, the cell diverts oleoyl-CoA into the ELOVL-CerS2 axis, swelling the Cer 24:1 pool.
- Result: Cer 24:1 ≈ 11.8 µM, far above the ≤9 µM longevity target—even though saturated ceramides are modest.
How to break the “oleate → nervonyl-ceramide” faucet
Retest Cer 24:1 after 8-10 weeks: the number should fall if elongation flux is rerouted or the peroxisomal “burner” is sped up.
What Fire In A Bottle says about SCD-1 and MUFA “toxicity”
Brad Marshall’s blog series “The SCD1 Theory of Obesity” argues that the enzyme stearoyl-CoA desaturase-1 (SCD-1)—which inserts a single double bond to convert saturated 18-carbon fat (stearate, 18:0) into oleate (18:1)—is a metabolic throttle. His core claims, gleaned from the posts linked below, are:
Mechanistic picture Marshall paints
-
SFA → MUFA conversion by SCD-1 lowers the FADH₂ : NADH ratio delivered to complex II of the ETC, reducing mitochondrial ROS.
-
Low ROS fails to trigger “adaptive thermogenesis,” so calories are stored rather than burned.
-
Oleate (18:1) itself acts as a ligand for SREBP-1c and PPAR-γ, up-regulating the very lipogenic genes (including SCD-1) that make more oleate.
-
Excess MUFA in membranes makes them more fluid, further activating SCD-1 in a feed-forward loop.
-
End result: high DI18 → depot fat more unsaturated → low metabolic rate → obesity/torpor phenotype.
In his framework, MUFA is not intrinsically poisonous the way he sees linoleic acid (PUFA), but becomes “toxic” in energy balance terms because it is the biochemical enabler of fat storage when SCD-1 is up-regulated.
Practical prescriptions he recommends
Lower SCD-1 expression
Huge reduction in linoleic acid (seed oils) because LA up-regulates SCD-1.
Eat very saturated fats (beef suet, cacao butter, stearic-acid supplements).
Consider natural SCD-1 inhibitors: sterculic acid (sterculia oil), berberine.
Keep MUFA low unless energy demand is high; replace extra-virgin olive oil with tallow or butter in a “Croissant Diet”-style pattern.
Track DI18 via an OmegaQuant RBC test; shoot for DI18 < 0.1.
How that intersects with your ceramide issue
High SCD-1 activity means more oleoyl-CoA substrate → elongated to 24:1 → Cer 24:1 buildup (exactly what you’re seeing).
Fire-in-a-Bottle’s solution—cut MUFA + inhibit SCD-1—would theoretically shrink the oleate pool that feeds Cer 24:1.
Your earlier plan (PPAR-α activation + peroxisomal burn + omega-3 balancing) tackles the disposal side; Marshall’s approach tackles the supply side. They’re complementary: less oleate in + faster VLC-FA burn = lower Cer 24:1.
TL;DR
Fire in a Bottle frames SCD-1-driven MUFA accumulation as a root cause of modern metabolic “torpor.” Oleate isn’t a direct toxin like trans-fats, but in his model it’s the lubricant that lets fat storage and insulin resistance accelerate. His antidote: slash linoleic acid, cap MUFA, push saturated fats, and pharmacologically (or botanically) inhibit SCD-1. That dovetails with your goal of dropping Cer 24:1 by squeezing both substrate supply and peroxisomal disposal.