Hyperlipid by Petro Dobromylskyj

08 July 2020

You need to get calories from somewhere, should it be from carbohydrate or fat?
  • Pesky PSCK9 inhibitors (2)
    Eric put various links in the comments to the first PSCK9 post leading, eventually, to this study:

    Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease

    which gives us these results:

    "Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P = 0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P = 0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P = 0.003)."

    and the conclusion:

    "These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non–lipid-related cardiovascular risk factors."

    Well. There we go. Again.

    Soooooo. What is the glaring omission from the study results?

    That's correct, there is no body count. Presumably the paper was written by cardiologists and/or lipidologists.

    Perhaps we should get a body count.

    Lets go to UK Biobank and some folk in Denmark. Here we have


    "In causal, genetic analyses, a 0.5-mmol/l (19.4-mg/dl) lower LDL cholesterol was associated with risk ratios for cardiovascular and all-cause mortality of 0.79 (95% confidence interval [CI]: 0.63 to 0.99; p = 0.04) and 1.02 (95% CI: 0.94 to 1.12; p = 0.63) in the Copenhagen studies, 0.79 (95% CI: 0.58 to 1.08; p = 0.14) and 0.98 (95% CI: 0.87 to 1.10; p = 0.75) in the UK Biobank."

    and in conclusion:

    "Genetically low LDL cholesterol due to PCSK9 variation was causally associated with low risk of cardiovascular mortality, but not with low all-cause mortality in the general population."

    Note, particularly that in the UK Biobank data, there was no significant risk reduction for CVD events in addition to the no, zero, zilch, nil reduction of risk in all cause mortality. None. I'm a subject in UK Biobank.

    So why would anyone expect PSCK9 inhibitors, certainly in the UK, to do any better than genetic PSCK9 activity reduction?

    Perhaps such people have a drug to sell in a broken paradigm.

    Peter
  • Protons (54) The miracle of fish oil
    This paper has absolutely nothing to do with obesity:

    Feeding into old age: long-term effects of dietary fatty acid supplementation on tissue composition and life span in mice

    The researchers fed mice on chow until 450 days of age. For some they then started blending in sunflower oil (omega-6 based) and for others they added in fish oil to the same chow. The composition of the diets was sufficiently similar that there was no effect on lifespan found, either median or maximum. But there was an effect on bodyweight. I bring this up because, while corn oil would be reasonably expected to be obesogenic, fish oil certainly would not.

    Unless you view it from the Protons perspective of course. Here the mitochondrial oxidation of omega-3 PUFA should be more obesogenic than omega-6, which is almost never the finding in rodent studies and which is why, over the years, I collect any studies which suggest this. To confirm my bias.


    Crucially the people running this current study were interested in longevity, not obesity.

    Despite this, not only did they weigh the mice weekly (which most studies do) but they also reported those weights in detail (which many don't).

    "Mean body weights in all three groups (over the entire experiment) and SEMs were 30.9 ± 0.1, 29.9 ± 0.1 and 28.7 ± 0.09 for n-3 rich, n-6 rich and controls, respectively."

    Graphically it looks like this:

















    If we take the rather crowded data points over in to PowerPoint we can crudely rough in some curves:












    The red line is the fish oil group, yellow the sunflower oil and blue the chow.

    Fish oil should make you fat. Confirming this bias is remarkably difficult, so you can imagine how I feel about these data points.

    Quite how fish oil can be shown to be so beneficial most of the time is beyond me. I think the aphorism goes something like "current medical research reflects current medical bias". Possibly from John Ioannidis?

    Peter

    Of course the fish oil mice might have looked like Arnie on steroids. Or they might not.
  • Pesky PSCK9 inhibitors
    For a variety of reasons I'm rather ignoring the blog at the moment. But this is too good not to post, HT to Carlos Monteiro for the link:

    Serious Adverse Events and Deaths in PCSK9 Inhibitor Trials Reported on ClinicalTrials.gov: A Systematic Review

    PCSK9 inhibitors do not work. However much they cost, they're useless.

    This confirms (again) that the lipid hypothesis of CVD is bollocks. It was so in the 1950s. Nothing has ever changed that.

    Happily only Evolocumab will kill you prematurely (with the data so far).

    Peter

    EDIT cavenewt emailed me this press release (see her comment for quotes). Permanent alteration of your PSCK9 gene... what could possibly go wrong? END EDIT
  • ARDS and Tucker Goodrich
    Tucker has been very, very busy over the last few weeks.


    You will need some time. Maybe some coffee.

    Peter

    Total, utter aside:

    "Although we initially also identified monoclonal antibodies that appeared to bind exclusively to 4-HNE-LDL, these were lost during the cloning procedure."

    The first ever auto immune disease to be tied to a specific human leucocyte antigen receptor subtype was ankylosing spondylitis, linked to HLA B27. The monoclonal antibody was developed by my wife's PhD supervisor working in Prof Ebringer's lab, as part of her own PhD. She lost it during the cloning procedure. It happens. As Tucker says:

    Bummer.
  • Blood "energy" content
    "One-liner" post. This is exciting (picked up on twitter from Mike Eades):

    Effects of dietary carbohydrate content on circulating metabolic fuel availability in the postprandial state

    It's Ludwig's group. I've skim read but not looked at the detail. I like what I see.

    Over the last year or so I've ventured in to the morass of older papers about the CNS response to infusion of various metabolic substrates where you get bogged down in the various neural groups which respond in various ways to high vs low glucose etc. It's messy and it's rare for people to have asked the questions in quite the way I might have phrased them.

    Eventually I simply started adding up the energy content of "blood" in various states, especially under extended fasting when hunger becomes blunted. Being me I tended to add them up in terms of how much NADH and FADH2 might be available. I kept getting pushed towards the idea that hunger might be a simple matter of the energy content of the blood supplying the hypothalamus. Clearly that is one core thing that the CNS monitors (using ROS of course).

    Could hunger be this simple?

    Okay, there is also clearly a neural input (think hepatic FFA infusion via the portal vein suppressing food intake) but ultimately if the brain is being perfused with too few calories, it is going to do anything it can to make you eat. The classic is reactive hypoglycaemia or insulin induced hunger where I suspect the problem is (in myself in pre low carb days) not absolute hypoglycaemia (I could get this at BG around 4.5mmol/l) but the accompanying low FFA availability giving low brain stem energy availability. But of course measuring FFAs is not as simple as measuring glucose...

    Anyway, it's fantastic to see some serious researches looking at the concept of blood energy content. They will have to add the Protons concept eventually, to explain why things happen as they do, but they're on an exciting trajectory.

    Peter