May 28

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

May 20

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.

Apr 19

LMHR Case Study – Genetics

In our recent Lean Mass Hyper-Responder (LMHR) case report, we performed extensive genetic testing on the subject, LM, and activity sought input from clinicians and geneticists outside the research team. Because of the broad nature of our testing and absence of notable findings, as determined by expert consultants, and manuscript length limitations, we stated in our publication: “Whole exome sequencing performed by Veritas Genetics, and independent dyslipidemia and ASCVD genetic risk testing by GB Healthwatch, revealed no pathogenic or likely pathogenic variants that could account for LM’s phenotype.”

As part of our continued commitment to open and transparent science, we are happy to disclose what results we can. But before doing so below, it is important to highlight two caveats:

1. While a whole exome sequence was ordered, it would obviously be inappropriate to release the entire Variant Call Format file. This represents the subject’s actual genetic code and to disclose the code would be a serious infringement on the subject’s privacy, and one that could potentially be used to his disadvantage in future. Thus, calls for access to the complete raw exome sequence by individuals not part of the patient’s care team will not be entertained.

2. Given the scope of the genetic testing performed, it is inevitable variants will be found. Every person carries risk variants. The important question is whether variant can explain the clinical and metabolic (LMHR) phenotype at hand. By way of example, a risk variant for elevated triglycerides is not clinically relevant if the subject’s triglycerides are 40 mg/dl.

Moving onto the genetic findings: In addition to the exome sequence with professional geneticist interpretation, we also ordered a Dyslipidemia and ASCVD comprehensive risk panel — the same one that is being ordered for the LMHR prospective trial (recruitment underway) and that includes the following targets: LDLR, APOB, PCSK9, LDLRAP1, LPL, CETP, LCAT, LIPC, LIPE, LIPG, LPA, PPARG, STAP1, ABCA5, ABCA6, ABCG5, APOC2, LMF1, GBIHBP1, CREB3L3, GCKR, SCARB1, ABCA1, APOA1, APOA5, BHMT, CBS, MTHR, MTR, MTRR, PEMT, SHMT1, GUCY1A1, ITGB3, MEF2A, NOS3, PLA2G7.

As shown below, and consistent with the published text, testing by GB Healthwatch, “revealed no [0] pathogenic or likely pathogenic variants that could account for LM’s phenotype.”

In terms of variants not classed as pathogenic/likely pathogenic, there were no variants in genes classically associated with familial hypercholesterolemia at levels seen in this patient: LDLR, APOB, LDLRAP1, or PCSK9. Overall, six potentially notable variants were identified, as follows:

Pathogenic and Likely Pathogenic Variants (0) and Variants of Uncertain Significance (VUS) and High-Risk Variants, provided by GB Healthwatch

  • ABCG8 521G>A, heterozygous VUS for sitosterolemia. Sitosterolemia is a condition in which plant sterols and other sterols can be hyperabsorbed. Given that this is a hyperabsorption disorder, the mainstay of therapy is dietary restriction of both cholesterol and plant sterols. Of note: (i) testing performed on LM on October 20, 2021 confirmed normal campesterol levels at 8.2 mg/L. (ii) Most importantly, a hyperabsorption phenotype is inconsistent with the clinical presentation. As reported in the manuscript, when hyperabsorption was considered in the case of LM, “LM was recommended to reduce dietary cholesterol intake, eliminating liver, shellfish, and egg yolks from his diet (in substitution for lean chicken, fish, and egg whites). One month later, in September 2020, his LDL-C was remeasured at 545 mg/dl (HDL-C 94 mg/dl, TG 58 mg/dl).” Thus, LM’s dietary cholesterol intake was lowest when his LDL-C was at its peak, and hyperabsorption cannot account for his LDL-C phenotype on a carbohydrate restricted diet.
  • APOA5 3’UTR, heterozygous variant and risk factor for hypertriglyceridemia. The patient’s triglycerides ranged from 39 – 58 mg/dL. Again, the risk variant is inconsistent with the metabolic phenotype.
  • CBS 133C>T missense heterozygous VUS for homocystinuria. LM has no clinical signs of this disorder and homocysteine last measured January 3rd 2020 normal at 9.7 umol/L.
  • CDKN2B-AS1 22124478A>G homozygous variant that codes for an altered form of a long non-coding RNA that is associated with increased risk of myocardial infarction in some studies. While this variant does associate with increased risk of myocardial infarction, the increased risk does not appear to be driven by alternations in blood lipids, including LDL-C and there is no reason to believe it contributed to the patient’s phenotype on a carbohydrate restricted diet.
  • LPL 953A>G heterozygous variant that has been linked to increased risk for hypertriglyceridemia. As noted, the patient’s triglycerides ranged from 39 – 58 mg/dL. Again, the risk variant is inconsistent with the metabolic phenotype.
  • SLC22A1 1022C>T heterozygous variant and risk factor for elevated Lp(a). As stated in the report, Lp(a) was high in the subject prior to adopting a ketogenic diet and is elevated in the patient’s father. This allele is presumably paternally inherited and there is no reason to believe it contributed to the patient’s LMHR phenotype.

In addition to the targeted genetic risk panel, a 144-page report corresponding to the exome sequence also revealed no known pathogenic or likely pathogenic variants for heart disease. Under “important” risk variants, the patient was noted to be a carrier for HFE 845G>A for hereditary hemochromatosis, MEFV 442G>C for Familial Mediterranean Fever, and MMP2 524G>A for multicentric osteolysis, nodulosis, and anthropopathy. These are all autosomal recessive conditions, and the patient does not present with signs or symptoms of any of these disorders. Homozygosity for lactose intolerance was also noted.

Under “noteworthy” variants, 7 variants were identified for cancer risk, 3 for clotting disorders, 4 for neurological disorders, 4 for other organ health, and only one for cardiovascular disease. This variant was in KCNE1 with classification of “no known risk” (VUS), for long QT syndrome, as detailed below. Taken together, the exome sequence revealed no notable findings that could explain the patient’s LMHR phenotype.

Thus, these genetic data provide no means by which to explain the patients presentation, defined by a shift from normal LDL-C of 95 mg/dl while on a mixed macronutrient diet to an LMHR triad of LDL-C 393 – 545 mg/dl, HDL-C ~115 mg/dl, triglycerides ~40 mg/dl. In fact, several of the identified variants were associated with increased risk for hypertriglyceridemia, which is in obvious contrast to the patient’s presentation.

In summary, our interpretation is that, while one cannot rule out genetic contribution or modification, the evidence at hand is most consistent with the hypothesis that the LMHR phenotype is driven by non-genetic factors including leanness and dietary macronutrient composition. More details on the Lipid Energy Model will be forthcoming shortly.

Apr 17

New LMHR Case Study Published

We’re happy to announce the release of our new LMHR Case Study this week in Frontiers in Endocrinology. Feel free to download the PDF and share the page link if you find the paper compelling. (The more our work is shared, the more it supports our efforts, of course.)

Highlights of the new paper:

  • LDL-C increased from 95 to 545 mg/dL at its peek
  • Keto diet is “Mediterranean” style with >4:1 unsaturated to saturated fat ratio
  • No genetic abnormalities found to explain phenotype
  • No detectable plaque in CT Angiogram after 2.5 years of followup

Our video abstract here (7 minutes):

Apr 05

Comment on: Mark’s “Making of a LMHR”

Recently, Mark Lightell, a 29-year-old endurance athlete, took it upon himself to try to convert to the LMHR phenotype with a two-week n=1 experiment. You can find Mark’s post about this experience here. Mark and Dave invited me to do a little commentary on Mark’s experiment. Here it goes…

First, I want to reinforce my respect for Mark’s scientific curiosity. As I wrote in my closing note to Mark’s post, “[T]he fact that Mark’s personal hypothesis leans towards isolated high LDL-C being sufficient to drive atherosclerosis (and, thus, less in line so with some in the LMHR community) does not preclude him from sharing a genuinely scientific interest in the LMHR phenomenon, nor should it. This n =1 experience is a testament to how those with different hypotheses can share scientific curiosity and collaborate in genuine attempts at pursuing scientific truth.” In fewer words, “GO Mark!”

With that, some thoughts…

Study Duration

Mark’s hypothesis was that “adherence to a very low carb ketogenic diet will produce a LMHR profile within a timespan of 2 weeks.” While the half-life of LDL particles would suggest a full conversion to the LMHR phenotype (LDL-C ≥ 200, HDL-C ≥ 80, and TG ≤ 70 mg/dL) could be possible in two weeks, I think it’s first important to consider the impact and timeframe of fat-adaptation.

The Lipid Energy Model (manuscript for publication in production) proposes that the high LDL-C observed in LMHR is driven by dependence on fat as fuel and on the LPL-mediated turnover of hepatically secreted VLDL. That’s a jargony way of stating that the LMHR phenotype is most likely to be exhibited in those who are fully fat adapted.

While Mark’s endurance exercise regimen suggests that his body should be good at oxidizing fat at baseline, the fact that his body was completely naive to carbohydrate restriction also means he probably did not achieve full fat adaptation within 14 days of starting a ketogenic diet. Of course, he did see a trend towards the LMHR phenotype (a doubling of LDL-C from 68 to 139 mg/dL) consistent with what the LEM would predict in an individual who is in the process of fat adapting, and upregulating VLDL secretion and peripheral turnover.

There are, of course, other explanations. For instance, synthesis of ApoB could have been rate-limiting, creating a metabolic bottle neck for the repackaging and export of non-esterified fatty acids upon VLDL, to be converted into LDL by LPL. Again, this is a jargony way of stating, metabolic change takes time, and I’m not sure one should expect full conversion to LMHR in two weeks.

Vegan Diet Baseline

The choice of both the baseline diet and the ketogenic diet were interesting. With respect to the baseline diet, it was Mark’s choice to consume a vegan diet to lower his LDL-C as much as possible as a run-in phase, although he doesn’t regularly consume a vegan diet. As he has disclosed, his normal resting LDL-C on a mixed macronutrient diet rests at ~130 mg/dL. Thus, the transformation observed in his experiment could be interpreted as a reversion to his personal baseline.

It is pertinent to contrast this scenario (vegan diet to keto-carnivore diet) against much of the current LMHR community who have converted to the phenotype from a standard mixed diet after changing to many forms of ketogenic diets (standard to ketogenic). In other words, in this case, we can’t distinguish between the putative contributions of the ketogenic diet raising the LDL-C or the vegan diet lowering it. That evidently creates a major confound in data interpretation that is important to highlight.

Keto-carnivore Diet

As I was not consulted on the formulation of the baseline diet, neither was I consulted on the formulation of the on the ketogenic diet. Mark’s ketogenic diet reflected Dave’s standard diet and included Colby Jack Cheese, Beef Franks, Hard boiled eggs, Diet Coke, with the addition of uncured bacon… for variety (that’s a laugh line folks). Mark explains that he “found the diet intolerable” and “had a miserable time.” All I have to say to that is, I probably would have reacted the same way.

Quickly, for those of you who don’t know, Dave and I are quite close and I love him like a brother. So, what I say next is written with a comedic tone (but with honesty): Dave’s diet makes me sad. Sometimes, after a nice dinner of smoked salmon with capers, roasted garlic, buffalo mozzarella and extra virgin olive oil, and dark chocolate with coconut manna for dessert, Dave and I will get on a Zoom call and I’ll see him munching on a piece of string cheese with a Diet Coke and my tongue will cry a little for him.

Point being, I don’t blame Mark for quitting the Dave diet after two weeks, especially when his gut had recently been adapting to veganism. (Talk about a shock to the microbiome! – It’s like tossing a giraffe into the arctic). The fact that he lasted two weeks is a testament to his strength. But the more serious point I want to make is that Dave’s diet is not necessary or typical of LMHR. You can be an LMHR while eating vegetables or without eating meat or eggs.

So, to Mark: I’m sorry.

To Dave: You and I need to have a little chat about both your diet and – more pressingly – sleeping habits.

And to readers: We will shortly have for you a rather striking demonstration of how the LMHR phenotype can occur in the context of a low-saturated fat ketogenic diet. Let’s put a pin in that…

“Picking up the torch”

In his post, Mark expresses a desire for someone to “pick up the torch” and replicate his attempt to prospectively convert to LMHR, albeit over a greater time frame. I can here confirm that is being done. We have another community member who has self-selected to attempt to convert to LMHR over the next couple of months. Like Mark, she’s young, athletic, and by all measures metabolically fit with a baseline LDL-C on a mixed diet (not vegan) of 50 – 79 mg/dL. (Some other markers: HDL-C 73 mg/dL, TG 50 mg/dL, HbA1c 4.8%, insulin 4.9 uIU/L, BMI 24 kg/m2.) I think we will all be interested to see what happens.

Of course, these n = 1, while prospective, are not properly designed clinical trials. Hopefully, we will acquire the partnerships and resources to conduct these after publication of the Lipid Energy Model manuscript. Already, I’m noting more serious researchers within academia approaching us about this work. The ball is starting to pick up steam…

But, circling back to the point I made above, the most notable thing to me about individuals like Mark and our anonymous second subject is that their self-directed efforts represent an interest in a scientific curiosity (the LMHR phenotype) sufficient in magnitude to compel them to put their tongues, guts, and bodies on the line to pursue science. If that’s not being a citizen scientist, I don’t know what is.

Other Lab Abnormalities

As a final comment, Marks labs were also notable for several abnormalities, including but limited to leukopenia (WBC 2.2 – 3.0 x10e3/uL) and elevated bilirubin throughout the vegan and keto-carnivore stages, and thrombocytopenia while vegan (PLT 127 x10e3/uL). These abnormalities were largely pre-existing and we have reinforced his doctor position that he pursue a hematology consult. It’s important to acknowledge these other abnormalities, not only for their potential interaction with the results, but also to strongly caution others against embarking on dramatic lifestyle changes without professional consultation when one is aware of pre-existing conditions, especially dietary changes that may exacerbate pre-existing nutrient deficiencies.

Note from Dave: I laughed out loud when I read Nick’s comment above, “Dave’s diet makes me sad.” To be sure, Nick, that’s not actually my normal diet at all. The “baseline diet” is strictly for experiments and doesn’t include Diet Coke and bacon. But the three baseline components (+ vitamins & electrolytes) were selected against many criteria that includes availability and consistency when traveling, avoidance of preparation and/or cooking oils that could be confounding, and zero fiber – to name just a few. I wanted to get as few components as possible to achieve this baseline, and that’s where I landed. In short, it’s my version of a “ketovore chow” that has been very successful for replication of baseline bloodwork as well (such as with OxLDL Replication Experiment). We can discuss more in depth when we do a podcast on this experiment — should be fun! 😉