Thread by @TheCuriousAhmed

Lipoprotein lipase, the major player in the LMHR phenotype, apparent atheroprotection, despite higher LDL-C, thread.

To begin with; I was supposed to post this thread 2 weeks ago, but due to circumstances it was delayed.
This is an extensive thread comprised of 5 sections.

Section 1: discusses the mechanisms.
Section 2: the effect of insulin.
Section 3: the relationship with other blood markers.
Section 4: the effect of diet.
Section 5: the impact in atherosclerosis.
Section 6: longevity syndrome (separate thread - in progress)

Overview: LPL mediate the turnover of TG-rich remnants (VLDL) to cholesterol-rich particles (LDL), resulting in a phenotype characterized by high cholesterol and low TG or “lean mass hyper-responder” phenotype (LMHR).

Section 1: mechanisms for VLDL production and turnover.

The first life cycle of VLDL particles include esterification of free fatty acids (FFA) into triglycerides (TG), which are incorporated into VLDL particles by the hepatocytes.

The majority of FFA are a product of adipocyte lipolysis, and small portion is attributed to hepatic lipogenesis.

VLDL-TG is hydrolyzed by LPL to provide the cells with fatty acids.
When TG is depleted in VLDL particles, it becomes an LDL particle.
This is the primary catabolic pathway for VLDL.

LPL inhibition delay VLDL-TG catabolism.
Delayed VLDL-TG catabolism is associated with increased TG, low HDL, and small dense LDL (sdLDL).
ncbi.nlm.nih.gov/m/pubmed/32767…
(the mechanisms are described in the upcoming tweets)

Delayed VLDL-TG catabolism (via LPL) will shift VLDL-TG catabolism to a different catabolic pathway (CETP pathway), which is responsible for decreased HDL levels, and the generation of small dense LDL and HDL.

CETP mediate TG transfer from VLDL to LDL and HDL (in exchange of CE), resulting in TG-enriched LDL and HDL.

Hepatic lipase (HP) liberate TG from TG-enriched LDL and HDL, forming small dense LDL and HDL.
TG-enriched HDL is usually cleared rapidly, thus HDL is decreased.

In other words; high LPL activity promote increased turnover of VLDL particles into LDL, this might result in low TG (VLDL) and high cholesterol (LDL) and also prevent CETP activation, which results in higher HDL, and lower sdLDL.

Section 2: the relationship between LPL activity and other blood markers.

The following study, reported the correlations with the lipid markers
ncbi.nlm.nih.gov/m/pubmed/19117…

LPL activity positively correlated with LDL and HDL, and negatively correlated with VLDL and TG [table 5]
These correlations with blood lipids are expected.

The study also reported a negative correlation with serum insulin [r=-40, p=0.04, (table 6)], but how insulin infleunce LPL activity and therefore blood lipids?

Section 3: the effect of insulin.

LPL activity is correlated with fatty acid oxidation or “fat-adaptation”
ncbi.nlm.nih.gov/m/pubmed/83260…
(Fat-adaptation; when fatty acids are the primary fuel source)

So, LPL activity is a component of “fat-adaptation” or in other words, the requirement of fatty acids as fuel, will increase LPL activity. And in contrast, less requirement of fatty acids will decrease LPL activity, this is the case with insulin.

Insulin is known to stimulate the uptake of nutrients (e.g fatty acids) into the cells, therefore, in certain physiologic conditions, insulin activate LPL activity to mediate FA uptake into the muscles.

However persistent insulin stimulation inhibit FA oxidation in favour of glucose oxidation, thus LPL activity is decreased.
ncbi.nlm.nih.gov/pmc/articles/P…

Section 4: the effect of diet and CHO-SFA replacement.

It's a very common misconception that CHO increase TG due to excess lipogenesis, but actually excess lipogenesis is stimulated only when glycogen storage is filled.

So it's unlikely that increased TG to be a result of increased production, but due to decreased clearance, as reported in this study
ncbi.nlm.nih.gov/pmc/articles/P…

In the previous section, we elucidated that insulin is a crucial factor in modulating LPL activity, dietary carbohydrate is known stimulate insulin secretion, thus carbohydrate restriction is expected to increase LPL activity.

And this the case, low CHO diets increase and high CHO diets decrease LPL activity, as reported in several studies, for example:
ncbi.nlm.nih.gov/m/pubmed/67526…
ncbi.nlm.nih.gov/m/pubmed/64366…
ncbi.nlm.nih.gov/m/pubmed/35456…
The changes in LPL activity correlated with the changes in blood lipids.

Thus, increased LDL promoted by CHO-SFA replacement is attributed to increased VLDL to LDL turnover.

It's a common misconception that increased LDL induced by SFA-CHO substitution, is due to LDLr downregulation.

However this is not established, there's a conflict in animal and human studies, some studies suggest that the effect of saturated fat in LDLr is minimal
sciencedirect.com/science/articl…

PUFA increase LDLr, when SFA replace PUFA, LDLr is decreased.
In animal studies, dietary cholesterol is usually supplemented with SFA and dietary cholesterol decrease LDLr activity in animals.

However LDLr downregulation might indeed occur in response to increased VLDL turnover, however this is a normal physiologic condition to prevent lipid overload by inhibiting adipocyte lipolysis.

LDL act as a negative feedback signal to inhibit adipocyte lipolysis, because as illustrated in the first section, free fatty acids promote VLDL secretion
ncbi.nlm.nih.gov/m/pubmed/19020…

- The effect of SFA-CHO substitution.

There are 4 meta-analyses investigated the effect of CHO-SFA replacement in blood lipids.

[Clarke et al - 1997] and [Mensik et al - 1992] reported the most favorable in terms of the traditional lipids markers (LDL/HDL and TG/HDL ratios). [Mensik et al - 2003] reported less favourable effects. [Mensik - 2016] reported the least favorable effects.

The traditional lipids markers (LDL-C/HDL-C and TG/HDL-C ratios) provide a good surrogate for the composition of blood lipids; particle count, size, and overall the crucial marker ApoB.

So, even if HDL isn't indeed causal factor, HDL-C still provide a good estimation for particle count and size and concentration of the remnants.

And indeed in [Mensik et al - 2003] there was no significant effect to ApoB. however [ Mensik - 2016] reported a statically significant effect.

But unfortunately [Clarke et al - 1997] and [Mensik et al - 1992] didn't report ApoB concentration, although it's expected to be better based on the traditional lipid markers (highest increase in HDL-C reported with Clarke et al).

It's worth to note that, the RCTs from Mensik's meta-analyses were conducted in free living conditions, whereas Clarke et al conducted in metabolic ward conditions.

Based on the meta-analyses, we see a notable divergence between the studies in the effect of SFA-CHO in blood lipids, one example is the widely cited study conducted by Krauss et al that showed saturated fat significantly increased ApoB and sdLDL
journals.plos.org/plosone/articl…

Unlike in the meta-analysis, ApoB significantly increased, but no significant effect to ApoAI and HDL, also TG, sdLDL and CETP activity increased and TC/HDL and TG/HDL ratios are worsened, changes that are not usual when saturated fat replace carbohydrates.

Even though the same group published a study, with contradicting results, LDL-C increased by 0.44 mmol/L (16.85 mg/dL) but no significant effect to ApoB: (+0.002 mmol/L), TG decreased and particle size increased
ncbi.nlm.nih.gov/pubmed/9583838

This explains the divergence; the effect of SFA-CHO replacement in ApoB is dependent on baseline insulin sensitivity.

Saturated fat might be neutral or even exacerbate insulin resistance and hyperinsulinemia, which in turn might decrease LPL, and thus increase TG, sdLDL and ApoB, as it's the case with Krauss et al study.

Although further CHO restriction might reduce insulinemia and exhibit a positive effect to TG, sdLDL and potentially ApoB.

Section 5, The impact of increased LPL activity in atherosclerosis.

We are maybe familiar with the study released today, it was the reason I completed this thread today.
acc.org/latest-in-card…

The study demonstrated a genetic variation in LPL; decreased TG and ApoB and increased LDL-C and lowered CHD risk.

However we know from a previous mice studies, LPL overexpression, even without decreasing ApoB, by just decreasing TG-rich remnants, significantly decreases atherosclerosis.

ApoE-KO mice overexpressing LPL, had lower VLDL and total TG, and higher ApoB, LDL and HDL.
ncbi.nlm.nih.gov/m/pubmed/10484…
The transgenic mice developed 2-fold smaller fatty streak lesions.

Section 6 will be posted soon in a separate thread.

End of the thread.

It's worth to note that, the increase in LDL and ApoB wasn't significant, and HDL didn't increase as I reported. LPL increase HDL only when CETP resemble the human version.
ncbi.nlm.nih.gov/m/pubmed/93741…