The Problematic Paradigm of LDL-C, Part 8

Part 8 - An Energy Delivery Model: The Contrasting Presentations of Elevated LDL-C

Previous - Part 7 - An Energy Delivery Model: Efficient Triglyceride Uptake and An Increased Energy Demand

In the previous sections, we have discussed how triglycerides move through and are used by the body. While traditional paradigms suggest that it is almost entirely fat consumption that influences lipid profiles, we have seen the two major ways in which an energy delivery model better explains lipid behavior:

1 - Poor energy utilization by the cells causes excess triglycerides to return to the liver

2 – An increased reliance on stored body fat increases VLDL production in order to meet energy demands

The first example is a failure of the energy delivery system, in which energy being delivered can’t be properly stored or used. The second is robust utilization of the energy delivery system. In each case, energy delivery (that is, VLDL production) is increased. I’ll pull passages from my paper on the topic to further drive home how significant these difference are:

 

“The more common presentation of elevated LDL-C, and the one that continues to prop up the lipid-heart hypothesis, is that of an insulin-resistant individual with poor metabolic efficiency. This individual is often overweight or obese, often largely sedentary, and almost certainly overconsumes carbohydrates. Because this person frequently overconsumes carbohydrates, post-prandial triglycerides will often be elevated. Poor metabolic flexibility and insulin resistant downregulation of LPL leads to lengthier lipemia and poor triglyceride uptake. As such, chylomicrons must “trade away” triglycerides to HDL and LDL before hepatic uptake. This causes HDL-C to be decreased and LDL to become a greater target for hepatic lipase activity. The same pattern is observed with VLDL-triglycerides, which are poorly taken up at the periphery and inevitably exchanged for cholesterol, continuing to depress HDL-C and create triglyceride-rich LDL. VLDL production is also higher than desired, the result of hepatic insulin resistance, an increased flow of glucose to the liver, and increased hepatic triglyceride return. The elevated VLDL production, and thus elevated VLDL-C, eventually manifests in increased remodeling to LDL and therefore elevated LDL-C. Furthermore, because so many LDL particles are increasingly rich in triglycerides, they are inevitably acted on by hepatic lipase and recycled into the bloodstream as small, dense LDL. Thus, due to high chylomicron and VLDL production, poor triglyceride uptake, and frequent use of HDL as a trade partner, the resultant lipid profile is legitimately concerning – Low HDL-C, high triglycerides, and, yes, high LDL-C.”

 

This, in many words, describes the metabolically unhealthy person who sees their LDL-C rise due to an impairment of their energy (that is to say, triglyceride) delivery system. As we’ll see later and as is hinted above, this presentation of elevated LDL-C is associated with many negative health risks and markers.

Contrast the above with the metabolically healthy, low-carb individual who sees their LDL-C rise due to increased (efficient) utilization of the same energy delivery system. This person’s elevated LDL-C is not associated with any of these metabolic risks or ominous health markers:

 

“The less common presentation of elevated LDL-C, the one that cannot be explained by the lipid-heart hypothesis, is that of an insulin-sensitive individual with highly efficient lipid metabolism. This person is less likely to be overweight, more likely to be active, and, most crucially, consumes few carbohydrates. Because insulin sensitivity and the capacity to use fatty acids for energy are maintained, chylomicron-triglycerides (which will likely be lower in this case) are efficiently taken up at the periphery. Endogenous triglycerides are also taken up efficiently, and the VLDL that carry them are quickly turned over to form LDL. Because excess triglycerides do not persist in blood, there is no need to rely on HDL or LDL as a receptor. HDL-C levels are maintained and triglyceride-poor LDL, not subject to hepatic lipase activity, will remain larger and more buoyant. In fact, hepatic lipase activity will remain low in general, as insulin levels are low and there are very few triglycerides being returned to the liver. However, because this individual is not overconsuming calories or consuming many carbohydrates, they will be more reliant on endogenous triglycerides as a source of energy. This increases VLDL production but, in contrast to the first example, the VLDL-triglycerides are taken up efficiently and the VLDL are remodeled very quickly. Thus, despite an increased production of cholesterol-containing VLDL, measured VLDL-C and remnant cholesterol will remain relatively low. Instead, this increased production will manifest as elevated LDL-C, due to the much lengthier lifespan of the LDL particle. The resultant profile also features elevated LDL-C, but in this case is not of the same concern, as evidenced by low triglycerides levels, low remnant cholesterol, high HDL-C, and large, buoyant LDL particles.”

 

Below is a modified table from that same paper, outlining the two distinct presentations of elevated LDL-C and comparing them to a metabolically healthy person consuming some reasonable amount of carbohydrates. Note that “sdLDL” refers to the formation of the smaller LDL particles that were described in the prior section on inefficient triglyceride utilization. While cardiovascular risk is included in the table, it is not yet necessary to understand what causes disease risk to be increased, as that will be a future topic in this series.

 

	Poor Metabolic Health	Healthy Moderate Carb	Healthy Low/Zero Carb
Presentation	Overconsumption of carbohydrates, poor metabolic health, potentially overweight and/or inactive	Reasonable carbohydrate consumption, much more likely to be active and at a healthy weight, good metabolic health	Zero or near-zero carbohydrate consumption, good metabolic health
Insulin Levels	Chronically Elevated	Low to moderate	Low
VLDL Production	Increase in TG-rich VLDL due to return of excess triglycerides to the liver	No increase in VLDL	Increase in TG-rich VLDL due to reliance on stored body fat for energy
VLDL Utilization	Poor, leading to increased VLDL lifespan and TGRL	Good to excellent	Excellent
LDL-C	Increases secondary to increased VLDL production	No increase	Increases secondary to increased VLDL production
sdLDL	Preponderance of TGRL increases CETP activity and TG-rich LDL, which are hydrolyzed to sdLDL	Little to no genesis of sdLDL	Little to no genesis of sdLDL
CVD risk	Elevated, due to sdLDL and hyperglycemic/insulin-resistant environment. Highlighted by high TG/HDL ratio and other markers	Not elevated	Not elevated, due to lack of sdLDL/hyperglycemia/ insulin-resistance. Highlighted by low TG/HDL ratio and other markers

Part 9 - An Energy Delivery Model: The Downstream Consequences of an Impaired Energy Delivery System