When writing my article introducing lipoprotein physiology I scratched together the following hypothetical model of ‘harmonious lipoprotein physiology’ based around what I’d expect from a high-saturated fat diet, with low omega-6 PUFA, and a very low-carbohydrate intake.
Harmonious Lipoprotein Metabolism via a High-Saturated Fat, Very Low Carbohydrate Diet?
After complete adaptation to a diet high in saturated animal fats (75% calories), very low in carbohydrates (<25g/day), and centred around a hub of animal based proteins (20% calories) the following pattern of lipoprotein metabolism may predominate.
Exogenously derived triglycerides provide the majority of the body’s total triglyceride supply. These are delivered directly to the peripheral tissues from the digested saturated fats via chylomicrons.
Triglyceride contents are rapidly removed by highly active lipoprotein lipase (LPL) in well-conditioned and fat-adapted tissues, with high capacities of fat-oxidation and intramuscular fat storage.
Chylomicron remnants are efficiently returned to and absorbed by the liver, and quickly recycled providing the dietary-derived cholesterol and some of the lipoprotein components for LDL formation and forward cholesterol transportation to peripheral tissues.
VLDL production is low due to the endogenously balanced and finely regulated flow of plasma free fatty acids, amino acids, ketones and gluconeogenically derived glucose. LDL formation is therefore balanced and commensurate with peripheral demand for new cholesterol. ApoB100 lipoprotein particle numbers are stable and consistent. Pattern-A large buoyant LDL particles with generous anti-oxidant profiles predominate in circulation.
There is limited competition for binding with lipoprotein lipase at peripheral tissue due to low VLDL production and therefore triglyceride clearance rates are rapid. The significant reduction in VLDL appearance and their subsequent rapid clearance from circulation, leads to low lipoprotein particle delipidation and therefore negligible production of the atherogenic small dense LDL.
ApoB particles' triglyceride content should be low in polyunsaturated fatty acids due to the majority of dietary fats being fully saturated, with only essential amounts of polyunsaturated fatty acids for incorporation into peripheral cell membranes, thus reducing the potential for oxidised LDL formation.
Basal fasting blood glucose levels are low and post-prandial levels will not reach levels capable of causing glycation and the formation of AGEs within particles or to endothelial surfaces.
HDL particle numbers are elevated by the plentiful influx of dietary saturated fats, with low rates of catabolism, creating a high plasma HDL/apoB ratio. HDLs should therefore have no difficulty meeting the demand for their role as ‘apoprotein lending libraries’.
Excellent triglyceride clearance will negate the incapacitation of HDL by triglyceride saturation. Overall, HDL is able to carry out its very important anti-inflammatory, antioxidant and anti-thrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, without any obvious resistance.
End result - plaque free pipes?
After writing the above hypothetical scenario I found this beauty - “Modification of Lipoproteins by Very Low-Carbohydrate Diets” by J.S. Volek et al (2005).
The paper makes a similar, albeit far more precise, proposal of anticipated lipoprotein metabolism in response to a very low carbohydrate diet.
Volek et al propose the following model to explain the modifications in lipoprotein metabolism on a very low carbohydrate diet (VLCD):-
Proposed model of lipoprotein metabolism with consumption of a VLCD that explains the observed decrease in TAG, increase in HDL-C, and redistribution of LDL to a larger particle size. Paths upregulated during consumption of a VLCD are represented by solid lines and those downregulated by dashed lines.
Volek et al - “Repeated ingestion of a VLCD initially increases circulating TAG-rich chylomicrons, which are cleared rapidly by lipoprotein lipase (LPL) bound to the luminal surface of capillary endothelial cells in skeletal muscle and adipose tissue.
Although speculative, we suggest that a VLCD increases muscle LPL, enhancing TAG clearance. A VLCD leads to lower glucose and insulin levels, which decrease LPL and increase hormone-sensitive lipase (HSL), promoting TAG hydrolysis and increasing fatty acid (FA) rate of appearance.
LPL-mediated lipolysis of chylomicrons results in release of FA that is either taken up by the underlying tissue or escapes into the circulation. Any increase in FA delivery to skeletal muscle is balanced by an increase in fat oxidation as evident from the post-absorptive respiratory exchange ratios near 0.7.
Circulating FAs are taken up by the liver and preferentially diverted away from esterification to TAG and toward mitochondrial oxidation to acetyl CoA. Accumulation of acetyl CoA exceeding the capacity for mitochondrial oxidation results in the formation of ketones.
Reduced hepatic production of TAG results in less VLDL synthesis and secretion into the circulation.
LPL-mediated lipolysis of VLDL results in transfer of unesterified cholesterol, phospholipid (PL), apolipoprotein (apo)E, apoC-II, and apoC-III to form mature HDL-C. The remaining remnant particles are either taken up by the liver or converted to LDL.
Decreased circulating VLDL, particularly in the postprandial period, results in less cholesterol ester transfer protein (CETP)-mediated neutral lipid exchange with LDL-C. A reduction in hepatic lipase (HL) prevents larger LDL-C from being delipidated to smaller, dense (atherogenic) LDL, resulting in a predominance of larger LDL particles.”