Thread by @DaveKeto

1/ #ListeningThread

Two fantastic intellectuals, @robbwolf and @lipoprotein, chatting about lipids, cardiovascular disease, and #LMHRs

Good podcast for my evening walk — might add some thoughts here…

https://twitter.com/precisehlthrpt/status/1411003691793006592

2/ Wow, in the intro Rob mentions Bill having discussed LMHRs with me (and yes, we’ve had many great chats on the topic). Where he agrees, and where he disagrees. To be sure, I have a bit of an advanced preview on what that will likely be. ;) but I’m excited to hear it in the ep.

3/ 28:30 Bill: I think Dave Feldman has probably helped more than any one person in giving disability and how radically our bodies can change [lipid levels] in just days… So yeah, you can actually influence these results quite a bit in a 3 to 5 day period of time…

4/ … depending on how radically you’ve changed things over that period of time. So the expectation is – you should be in your usual state for at least a week or more.”

Music. To. My. Ears.

Yes — be mindful of what you’re consuming running up to your blood test…

5/ I’m incredibly happy to hear Robb and Bill discuss this – as I couldn’t be more opinionated on this topic.

In particular, it’s worth noting that if you drop your overall food consumption (particularly when keto) you may get a higher relative LDL result…

6/ … hence, it’s more likely the best decision to eat at your baseline levels leading up to a blood test so as to avoid perturbing it from where it would likely be in the overall.

7/ The kick off discussion on LMHR at around 1:03.

@robbwolf: "The problem that I've had with this is that when I've done back-of-the-envelope calculations of how much energy is being shuttled around in lipoproteins relative to triglycerides...

8/ ... I don't see how that's a really significant contributor there, and I asked Dave about that, I said, have you ever sat down and done the [calculations] on how many kcals of energy are locked up in all these classic lipoproteins relative to just the triglyceride fraction?...

9/ ..And he says, 'no'. And I said, well, that seems like an important thing to do."

🤔 With loving respect to my good friend, @robbwolf -- citation needed! 😂

I don't recall having this specific discussion... was it on our podcast?

Here's why I wouldn't say 'no' in general...

10/ The ability to calculate shuttled triglycerides onboard lipoproteins isn't achievable without extraordinary tracer studies given we can't track its relative proportions of uptake vs that of NEFA (non-esterified fatty acids) in this context, both in serum and transmigration...

11/ When someone is keto, how can we determine:
- % change in whole body lipolysis?
- Total hepatic NEFA uptake?
- % of hepatic FFA toward ketogenesis vs TG sythesis?
- % of adipocyte VLDL-TG uptake vs non-adipocyte?
- Relative change in lipoprotein lipase activity?

12/ Let me put it this way, if I could hire you to do the calculations and they were even close to the likely reality, I'd pay you a very handsome price! But I don't think we can even ballpark true trafficking and exchange dynamics without at least tracer studies in this context

13/ (And FWIW, I think the tracer studies would still have a lot of challenges, but we'll save that conversation when we can talk live next...)

14 Important section at 1:07:30:

Bill: "So I do think that a Lean Mass Hyper-responder is using energy differently than say an insulin resistant individual. An insulin resistant individual is getting a lot of this energy packed into adipocytes...

15/ "... in LMHR a lot of this energy is being used by muscle with less being packed into adipocytes / fat tissue. So that's one difference."

16/ "Another difference is the fact that a LMHR is insulin sensitive, and therefore they don't have a lot of egress of free fatty acids from their fat cells, just as background. Whereas an insulin resistant person has trouble holding onto the fat in their fat cells..."

17/ "They leach out free fatty acids on a regular basis, it goes into the portal circulation and hits the liver. The liver says, 'oh I can use this to make triglycerides' makes triglyceride, 'now I have to do something with the fat I've made' make more VLDL..."

18/ "Large VLDL particles are fat-enriched are sent out of the liver, that gets degraded into LDL. So part of the problem is that I have all this background substrate hitting the liver making more VLDL in the insulin resistant person."

19/ "That's a fundamental difference between a lean, and an insulin resistant individual. So just physiologically, they are different, and they are processing lipoproteins differently."

I want to stop here for a moment to discuss where my and Bill's hypotheses diverge...

20/ But before I do, I just have to say how honored I am to have moved the conversation this far with such a towering giant in the field. I have such tremendous respect for Dr. Cromwell and appreciate how much thought he's contributed to discussing this topic...

21/ Okay, everything he discusses with regard to an IR individual is spot on.

But while they are not yet comprehensively studied, I want to share my hypotheses as they relate to the #LipidEnergyModel that diverge from his description above...

22/ First, I posit #LMHRs are actually making very active use of their subq adipose. While certainly there is greater direct use by non-adipocytes (particularly myocytes) of ApoB-TG, I still think activity is still very substantial for staging and pacing of FFA availability...

23/ Fortunately, this is very testable as in time we (or some other team ) will do biopsies on LMHR adipocytes to look at relevant areas on this, such as LPL, Angptl3/Angptl4, GPIHBP1, etc.

If activity is low, this would knock down that hypothesis -- we'll see in time...

24/ Second, and perhaps more relevant, I think LMHRs have quite a bit of fatty acids being taken up at the liver as well, but are synthesizing and secreting ApoB-TG quickly, & successfully. This too is very testable. (If net TG secretion by LMHR liver is low-> knocks hypothesis)

25/ Now I need to get super extra geeky here for a second.

High HDL-C is also specific to the LMHR triad. But why would this marker increase so substantially?

I posit it is a strong proxy of post-LPL ApoB-TG turnover, with much of the PL, CE, and FC moving to HDL species

26/ Toward the end of the episode, they discuss the #HADLmodel

cc @zinocker

27/ Overall - this was a fantastic episode for lipophiles

Thanks again, @robbwolf and @Lipoprotein for putting this together.

There was way more covered than I discussed above, so for anyone reading this far who hasn't already queued it up, consider giving it a listen. 👍👍👍

Typo – obviously, he said “visibility on” not “disability and”