The New Cholesterol Code – Less Comments, More Research

Hello everyone!

You may have noticed we’ve been posting less frequently here at CholesterolCode.com (CC). This isn’t for lack of interesting things to share and update you on – it’s because Siobhan and I are now fully entrenched in both formal research through the CitizenScienceFoundation.org and expanding our blood testing service, OwnYourLabs.com.

A Quick Recap

Here’s a brief rundown of everything Dave been doing over the last year:

  • Four papers published on the Lipid Energy Model and the Lean Mass Hyper-Responder phenotype, including one first authored
  • Produced video abstracts on two of these papers (here and here)
  • Four presentations and eleven interviews
  • And, of course, extensive ongoing work with the LMHR Study out of UCLA

Here’s a brief rundown of everything Siobhan been doing over the last year:

The Developments We Hoped For

We’ve long used CC as a means to stay close to the community and help promote the research we would like to see happen. But each of these circumstances have changed –– in a good way.

Before, the community was small and it was uncertain how prevalent things like the LMHR phenotype were. Now, as of this writing, the LMHR Facebook group and its sister CholesterolCode Facebook group boast over 9,000 members each(!), and it’s very active in knowledge sharing.

Also, we previously wrote emails and visited NLA conferences in the hopes we could get researchers to help advance this science. Now we’re working directly with researchers on the endeavors we dreamed of, both in the publication of papers and running studies directly.

To put it simply, we’ve replaced our responsibilities in pitching these projects with actually doing them.

What’s Next for CC?

We’re going to continue to be an information hub for our research, such as hosting an active published papers page.

  • We’ll also continue to post major announcements here.
  • However, we don’t have the bandwidth we once did for actively responding to all comments. Thus, we’re going to be retiring the Questions Page, and will not be actively responding to comments on CC.
  • More of the key questions folks are looking for will be answered in our current and ongoing published research, such as the LMHR study. For other questions, consider reaching out to us on social media via Twitter (@realDaveFeldman, @siobhan_huggins), or tagging us in the Facebook groups.

Again, we can’t thank everyone enough for their continued support at getting our research where it’s at — there’s so much more to come!

Heading to Florida with Some New Pins in Hand (Get Yours Here)

I’m excited to announce I’ll be heading to the Keto Orlando Summit this weekend.

I’m also excited to announce we made some commemorative magnetic pins for this occasion to help fundraise for the Citizen Science Foundation. If you donate $25 or more (see below), we’ll ship you the pin directly, or I’ll actually hand it to you if you’re attending the conference since I’ll have them on hand there.

For more on the details, visit the official page for this drop at CSF

Start Here (Pinned)

Welcome to CholesterolCode.com. This site serves as an information and research hub for emerging data on cholesterol. particularly in the context of a low carbohydrate lifestyle.

If you know little to nothing about cholesterol ->

If you’re wanting to learn more about why cholesterol could be higher, particularly on a low carb diet, we present the Lipid Energy Model (LEM) ->

If you’re looking to better understand the risk associated with high cholesterol on a low carb diet->

  • While several articles on this site present a more “cautiously optimistic” perspective on cholesterol in the context of fat adaptation, we strongly encourage everyone to consider the conventional view as well. Consider reading The Case for Lower LDL on Low Carb by our colleague and co-investigator, Spencer Nadolsky.

If looking to understand the “Lean Mass Hyper-responder” profile ->

If you’d like to understand possible relevance of cholesterol and the immune system, you can read Siobhan’s overview article on the topic here or watch her presentation here

If you’d like to learn more about lipoprotein(a), you can watch Siobhan’s presentation on it here

Lastly — you can always just ask us anything our Questions Page. (Just be aware our site does not constitute medical advice and we always recommend consulting with your doctor.)

Lean Mass Hyper-Responder: Is it the saturated fat?

It’s a question that comes up again and again: Could Lean Mass Hyper-Responders (LMHRs) just be eating more saturated fat?

Rather than repeatedly answering this question in cumbersome Twitter threads, I thought I’d save both Dave and myself some time by consolidating 5 points that challenge the saturated fat hypothesis of LMHR:

1. Magnitude of effect. Many LMHRs exhibit LDL-C levels of well over 300 mg/dl. Mean levels from the LMHR participants in our cohort study were 320 mg/dl (Table 3), and we certainly have a handful with LDL-C above 500 mg/dl. I’m not aware of any data suggesting saturated fat intake, even at extreme levels, can cause increases in LDL-C to such an extent. If you – the reader – are aware of such data, please do share.

2. LDL-C change has an inverse relationship to BMI. In the same study, we observed that LDL-C change has an inverse relationship to BMI on a carbohydrate restricted diet. If this is the case and saturated fat was the primary driver of the increase in LDL-C observed, then the logical implications are either that there is a dose-response effect of saturated fat on body weight loss (i.e. saturated fat makes subjects leaner) OR that persons who are lean and adopt low-carb diets preferentially eat higher proportion saturated fat diets. For example, if we had three subjects, Jamie, Nicky, Leslie, and Amir with BMIs of 24, 26, 21, and 30, respectively, and they were all to adopt low-carb diets, Leslie would eat more saturated fat than Jamie who would eat more saturated fat than Nicky who would eat more saturated fat than Amir. 

3. The triad. A critical point is that LMHR are defined, not by LDL-C alone, but the triad of high LDL-C, high HDL-C and low triglycerides. Therefore, any complete model explaining the LMHR phenomenon must account for this triad. Thus, we must ask, could eating more saturated fat cause to the triad of markers seen in LMHR? (And that’s assuming LMHR eat primarily high-saturated fat low-carbohydrate diets.) In our study, mean levels were 320 mg/dl LDL-C, 99 mg/dl HDL-C, and 47 mg/dl triglycerides.

4. Adding back moderate carbs attenuates the phenotype. In the case series associated with the aforementioned study, six LMHR or near-LMHR subjects were instructed to introduce 50-100g/d carbs to help replenish hepatic glycogen and, via the postulates of the Lipid Energy Model, lower their LDL-C. No further instructions were given, i.e. subjects were not told to lower saturated fat intake. Nevertheless, all subjects exhibited substantial reductions in LDL-C, including one who exhibited a drop from 665 mg/dl to 185 mg/dl. Even if saturated fat intake occurred spontaneously (without instruction), it seems unlikely it could explain the magnitude of the effect. 

5. Case series. Although it is an n = 1, we published a case series of an individual consuming a ketogenic diet relatively low in saturated fat (~82% unsaturated, ~18% saturated). His pre-low carb LDL-C was 95 mg/dl. But following carb reduction, LDL-C rose to a peak of 545 mg/dl, despite relatively low saturated fat intake. Furthermore, LDL-C trended inversely with BMI and, when saturated fat intake was altered for experimental purposes, LDL-C remained concordant with the BMI trend and, thus, inconsistent with the prediction that saturated fat drives LDL-C change in this subject. Even if this is only a case report, recall that these data represent a real LMHR patient and are consistent with both the LMHR cohort study and the Lipid Energy Model.

Certainly, none of these 5 points dispute that saturated fat could contribute to the increase in LDL-C seen in LMHR; however, they do suggest that saturated fat is not the primary driver of change. Disregarding point 5, could high saturated fat intake be permissive or even required for the LMHR phenotype? Possibly. However, unless one can explain how saturated fat intake could account for these data, we should assume there is more at play worth investigating. 

For more reading and viewing:

References:

Lipid Energy Model: https://www.mdpi.com/2218-1989/12/5/460

Lipid Energy Model video abstract: https://youtu.be/AkzxESsTJyM

Lean Mass Hyper Responder study: https://academic.oup.com/cdn/article/6/1/nzab144/6446805

Lean Mass Hyper Responder video abstract: https://youtu.be/v4FXBtVXPhA

Lean Mass Hyper Responder Case report: https://www.frontiersin.org/articles/10.3389/fendo.2022.830325/full

Lean Mass Hyper Responder Case report video abstract: https://youtu.be/JSEqIsYBZxU

Lipid Energy Model Published

We’re excited to announce the publication of the Lipid Energy Model in Metabolites.

The Lipid Energy Model (LEM) examines the phenomenon of rising cholesterol levels for those on low carbohydrate diets and how this may provide powerful insights into lipid metabolism overall.

The LEM provides a mechanistic explanation for:

  • The Lean Mass Hyper-Responder (LMHR) phenotype, characterized by the triad of high LDL (at or above 200 mg/dL), high HDL (at or above 80 mg/dL or above), and low triglycerides (at or below 70 mg/dL), as well as for
  • The phenomenon that LDL-C change on low-carbohydrate diets tends to associate inversely with BMI.

The LMHR phenotype and observation that leaner people with better metabolic health markers are possibly at greater likelihood for increases in LDL-C were described in our prior observational cohort study: https://doi.org/10.1093/cdn/nzab144.

We have also recently provided a particularly comprehensive clinical vignette of an LMHR: https://doi.org/10.3389/fendo.2022.830325

As a personal aside from the first and last authors (Nick Norwitz and Dave Feldman), while we’ve longed looked forward to this milestone, we wish to note that this is just the first of many. Interest in LMHR continues to grow, not only within the low-carb community, but within academic medicine. The publication of the LEM hypothesis paper is a landmark, not because it provides a comprehensive theory with rigorous support from human trials assessing the model, but because it presents a concrete hypothesis with direct and testable predictions.

It is our hope that the publication of the LEM paper (version 1.0) will encourage fellow researcher to help us test these ideas in interventional trials and, thereby, advance scientific knowledge regarding LMHR and, perhaps, human lipid metabolism more broadly.