Presenting on Lipoprotein(a) For Low Carb Houston

As some of you may know, I got the opportunity to present on the topic of Lipoprotein(a) for Low Carb Houston 2019. Just this past week the video was released, and is now available to view!

This can basically be thought of as an improved, fleshed out update of my Big Deal About Lipoprotein(a) post, so if you’re curious about my thoughts on lipoprotein(a) I’d recommend giving it a watch!

I also provide some data from some of my own experiments, including my pork versus beef experiment, and experiments showing lipoprotein(a) following LDL-C e.g. during the protocol.

As always, discussion is welcome especially as this is a topic that’s far from closed – there’s still plenty to learn and I look forward to doing so as more work is done to understand – the still quite mysterious – lipoprotein(a).

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Matt Cantley
Matt Cantley
19 days ago

Hi Siobhan,
Thanks for your work. I see cross over in yours and Dave’s research with my own investigations of the literature. I believe there is sufficient evidence in the last 40 yrs of lipid research to suggest low LDL-C, via intensive therapy, can decrease the resilience of HDL to oxidative insults. In a high risk study population I think it is well demonstrated that endogenous MPO-cascade insults (associated with atherosclerotic burden) can damage apo E. As you note, apo E is recycled from early endosomes in hepatocytes and macrophages, and is transferred between TRLs and HDL in to maintain supply and demand post prandially – Apo E being essential to CM clearance via the liver.

Matt Cantley
Matt Cantley
16 days ago

Hi Siobhan,
Fav paper?…A substantial amount :). It’s one of a few pillars underlying 3 reviews i have written and thoroughly referenced. Oxidative insults (HOCl, VPO1 etc) first push apo E into dimers with themselves and with apo AII so as to protect vulnerable amino residues. This is maintainable as long as there are core antioxidants in the lipoproteins. Once antioxidants are consumed by the insult damage to apo E then begins. Note it’s the total of any antioxidants in all lipoproteins of shared locality to said insult – lipophillic antioxidants are caried by only a tiny subfraction of the HDL pool; a few HDL must protect all. It is further complicated by the ratio of tocopherols and carotenoids; enriching some more than others promotes lipoprotein oxidation (several studies in-vitro, one in-vivo in humans), and further HDL seems the most susceptible to this. I don’t have an academic institution behind the work, or funds sufficient to pay for peer review through say plos one or frontiers. Yet the papers are polished with all the references you seek properly associated. I’m more than happy to email them to you if you wish to read and follow the references down the rabbit hole :P. I’d appreciate the feedback actually. All the best

Matt Cantley
Matt Cantley
11 days ago

Thanks Siobhan, I hope you find them interesting. I just sent them through to the above address…

Chris
Chris
19 days ago

Would you please share a link to the study showing Lp(a)/CRP risks? Unfortunately it is not mentioned in the slides

Matt Cantley
Matt Cantley
19 days ago

Intensive therapy may alter the portioning of dietary antioxidants into lipoproteins at the enterocyte through SREBP2/MiRNA33 induction, when combined with NPC1L1 & SRBI inhibition (ezetimibe) or antioxidant and cholesterol capture (bile sequesterants). I think i have demonstrated it is plausible that in clinical trials of high risk patients such inhibition may reduce resilience of HDL to MPO-cascade insults, resulting in increased apo E oxidation upon HDL2. This damaged apo E, preferentially transferred to CMs, could then result in increased CM remnant residence and the accumulation of VLDL1 behind them due to CMs hoarding LPL and HDL apos. Accumulating TRLs and the increased plasma FFA accelerates CETP transfers with HDL, causing HDLC catabolism (preferentially HDL2C). Increased VLDL1 residence directs more of VLDL into a remnant pathway rather direct clearance – ultimately increasing LDLC in the fasted state. Basically, the entire post prandial TRL metabolism cascade can be altered by just altering the positive to negative receptor ligand on CMs – of which oxApo E would be a double hit (and more if transfer seeded peroxidation). TRL remnants then evolve to be the trade partner post-prandially in place of HDL, (apo E & C’s move from preferential carriage in fasted state on HDL2 to VLDL remnants in hypertriglyceridemics). Further, the remnants have inactive LPL dimers and are apo E rich which draws CETP activity away from CMs (and a short intensive trade with them), prompting an extended scattershot of HDL CE trade with CMs through to IDLs.

Matt Cantley
Matt Cantley
19 days ago

I havent’ read the paper you showed about L(p)a, oxysterols and cancer; but in passing during my research I noted that cells taking up oxLDL have mitochondrial damage via oxysterols. I wondered, seeing that ectopic chain of F1-ATPase B1 is a HDL endocytotic receptor, why it takes in HDL and if dysfunctional/oxHDL may cause mitochondrial damage also…and if that could lead to cancer via Dr Thomas Seyfried’s metabolic theory of cancer? Does this protein, involved in ATP production; which spans the mitochondrial environment and beyond the cell membrane, draw in HDL in response to ROS, seeking HDL specific core-antioxidants like certain carotenoids? Or is it to receive instruction/update on the systemic energy stasis of the host via HDL carried MiRNAs? I noted how in SEAS trial of ezetimibe, there was a dramatic increase in cancer cases not seen in other ezetimibe trials which used high risk patients like ACS or kidney disease – phenotypes of known baseline HDL dysfunction. The SEAS population where normolipidemic aortic stenosis patients and so a completely different and arguably much less HDL ox stress at baseline. Seems reasonable that you won’t detect a change in cancer rate in a population where HDL can’t progress to markedly further dysfunction on-study… I haven’t investigated this at all, have written no papers on this point, I just think it’s another ‘interesting’ speculation 🙂 and deserves a closer look.

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