Addressing the HDL Problem in High Cholesterol Treatment

Cardiovascular disease is still the biggest cause of death in the developed world including the United States. One of the critical elements that influence this rate of death is the disruption of cholesterol homeostasis, especially in the context of increasing the risk of arteriosclerosis.1,2 One of the current principal medical therapies for managing high cholesterol is the administration of statins. However, while statins have demonstrated a relatively strong safety profile with minimal sides effects, there are individuals who are unresponsive to treatment or may prefer a different option. The chief influence of cholesterol concentrations is tied to both high-density lipoproteins (HDL) and low-density lipoproteins (LDL) concentrations. Stanins address the LDL side of the equation through their inhibition of HMG-CoA reductase; it makes sense that the next step in producing another effective form of cholesterol treatment is to focus on HDL.

HDL is one of five major lipoprotein groups that are responsible for transporting lipids like cholesterol, phospholipids and triglycerides. Both apolipoproteins, apoA-I and apoA-II, are required for normal HDL biosynthesis with apoA-I making up 70%.3 In contrast to LDL, HDL is responsible for moving lipids from cells, including within artery wall atheroma, to other organs for excretion or catabolism, most notably the liver.4 Both HDL and LDL concentrations are indirectly measured through the concentrations of HDL-C and LDL-C due to difficulties and costs associated with direct measurement. Since the 1970s HDL has been acknowledged as having a direct inverse relationship regarding risk for cardiovascular disease (CVD).5 This HDL-CVD relationship has also been conserved over different racial and ethnic populations.6 A seminal study known as the Framingham study also identified high LDL-C and low HDL-C levels as a strong predictor of CVD risk.7 Finally it has also been noted that close to 30% of lipids are transported by HDL in healthy individuals.8

The general belief is that HDL is able to lower the risk of cardiovascular disease through the inhibition and even reversal of atherogenesis via initiating the process of reverse cholesterol transport (RCT).9-11 RCT is the common term for the removal of cholesterol from peripheral cells and transport to the liver. While RCT involves multiple steps, the major ones involve the transfer of cholesterol from peripheral cells to HDL by ATP-binding cassette transporter (ABCA1) through apoA-I interaction and phospholipid interaction, conversion of cholesterol to cholesteryl esters by lecithin-cholesterol acyltransferase (LCAT) and the removal of these esters by interaction with either a direct removal pathway, scavenger receptor class BI (SR-BI), or the indirect removal pathway, cholesterylester transfer protein (CETP).4,10,11

CETP interaction involves the exchange of triglycerides of VLDLs with the cholesteryl esters of HDL resulting in VLDL being converted to LDL that later enters the LDL receptor pathway where the triglycerides are degraded due to their instability in HDL resulting in a smaller HDL lipoprotein that can begin to reabsorb new cholesterol molecules.12

The strategy of manipulating HDL concentrations or interactions to produce better health outcomes is certainly not unique and has not gone unnoticed by the pharmaceutical community. For example one of the initially more promising therapeutic treatments for high cholesterol was increasing expression of endogenous apoA-I due to its role in HDL synthesis. To this end some research has focused on using PPARgamma agonists to increase APOA1 gene transcription to eventually increase apoA-I concentration.13,14 ApoA-II has also received some attention because it appears required for normal HDL biosynthesis and metabolism. Increasing either apoA-I or apoA-II concentrations produce an increase in HDL-C levels and supposed HDL levels.

In contrast to increasing apoA synthesis rates, there is already effective means for increasing HDL-C levels via the supposed reduction of apoA catabolism through increasing nicotinic acid (niacin) concentrations.15 Niacin has demonstrated the ability to reduce HDL apoA-I uptake in hepatocytes in vitro.16 Whether or not this influence occurs via interaction with a HDL receptor or G protein-coupled receptors (most notably GPR109A), is unclear,16,17 but what is known is that niacin reduces apoA catabolism and increases HDL-C concentration.15

In addition to research on increasing HDL synthesis, other research has focused on reducing the degradation/loss of HDL through focusing on influencing the esterifcation and de-esterifaction HDL pathways. As mentioned above HDL-C is esterified to HDL-CE by LCAT. Low concentrations of LCAT in both humans and mice produce significant drops in HDL-C concentration and rapid catabolism of apoA-I and apo-II whereas high concentrations of LCAT result in significantly increased HDL-C concentrations.18,19 These results are more than likely due to feedback systems in that increased LCAT activity via higher LCAT concentrations increase conversion of HDL-C to HDL-CE, thus increasing the demand for HDL-C and its reactants (HDL and apoA-I/apoA-II).

Of the two major ending points for HDL-CE, labeling studies suggest that a majority of HDL-CE is transported to the liver via CETP exchange instead of through direct liver uptake via SR-BI.20 Therefore, CETP inhibitors, like JTT-705 and torcetrapib, are also viewed as an effective means of increasing HDL-C (and by association) HDL concentrations.21-23 Interestingly enough there also appears to be a negative influence on LDL-C concentrations.4,21 However, despite this increase in HDL-C concentration from CETP inhibition, there is a question of whether or not this pathway actually reduces CVD. For example large genetic and observational studies have contrasting results,24 but lean towards increased CETP concentrations increasing CVD probability, but inhibition of CETP does not seem to reduce CVD beyond standard rates (the reduction seen from not having elevated concentrations); this behavior may occur due to CETP negatively interacting with RCT.20

Overall despite the notion that higher native HDL levels (and higher HDL-C levels) are associated with lower rates of CVD and that all of the above methods have some ability to increase HDL-C concentration levels, pharmaceutical derived increases of HDL-C levels, be it from HDL-C direct increases, niacin, or CETP inhibition, do not instill the same CVD health benefits as native levels.25,26 Isolated genetic variants also appear to have little to no effect; for example a loss-of-function variant in LIPG raises HDL-C, but did not change CVD probability.26,27 So what could be a reason behind this inability of HDL-C concentration alone to decrease CVD probability?

One important element in the HDL pathway that has only been alluded to so far with regards to pharmaceutical intervention is the expression of the direct removal pathway through SR-BI. Various studies have identified that overexpression of SR-BI reduces HDL-C concentration and under-expression of SR-BI increases HDL-C concentration.28-31 Neither of these two results should be surprising as SR-BI is an end point pathway for eliminating HDL-C and/or HDL-CE converting it back to HDL. However, the interesting aspect of this change in SR-BI expression is that increased SR-BI reduces the rate of arteriosclerosis and decreased SR-Bi expression increases it.26 So how could SR-BI have this effect?

SR-BI, which is encoded by the gene SCARB1, was identified as the primary liver related HDL receptor decades ago.32 The principal role of SR-BI is to selectively uptake HDL-CE into hepatocytes and steroidogenic cells as well as, to a lesser extent, HDL-C.4,32 Most importantly the interaction between SR-BI and HDL-C(E) results in the internalization of the whole HDL resulting in the removal of the cholesterol and return of the non-cholesterol carrying HDL into the bloodstream.33

This absorption of HDL-C(E) and associated return of HDL could explain the reduced rate of arteriosclerosis over CETP interaction for among other things the SR-BI and HDL relationship trigger macrophage derived RCT.34,35 Basically SR-BI is returning HDL, not HDL-C(E) to the bloodstream which is ready to absorb more cholesterol; this readiness somehow signals the associated macrophages to induce greater rates of RCT. Whereas CETP does not reduce the cholesterol load of HDL as much due to the reliance on other limiting factors making them less capable of increasing RCT rates due to reduce cholesterol absorption capacity.

With this information about the functionality of SR-BI, a theory can be posited regarding why increasing HDL-C does not result in improved health outcomes. It makes sense to consider the idea that SR-BI is a form of limiting factor in the capacity of HDL to reduce the risk of CVD. Due to the fact that CETP appears to manage a majority of HDL-C(E) reduction it stands to reason that SR-BI expression is not significantly tied to HDL, HDL-C or HDL-CE concentrations. Therefore, when HDL or its cholesterol variants increase in concentration there is no corresponding increase in SR-BI. One possible explanation for this outcome is that a certain minimum concentration of cholesterol is required to circulate in the blood, which is managed by a level of negative feedbacks that maintain SR-BI expression levels at a certain floor and ceiling.

So why is SR-BI more important overall than CETP if CETP manages a majority of HDL reduction/eliminations? Perhaps CETP has a limit to what type of HDL it can manage. If HDL gets too “big” via its total level of cholesterol absorption the only means to remove that cholesterol could come from the direct pathway, i.e. SR-BI. However, if HDL concentrations outpace SR-BI expression by a significantly higher than normal level then it stands to reason that significant amounts of HDL will become too big for CETP to manage. Eventually these HDL molecules can breakdown (i.e. explode in a sense) while still circulating in the blood stream releasing all of the previously absorbed cholesterol and transformed cholesterol-esters. If this happens the cholesterol is not properly managed and can result in the increased the rate of arteriosclerosis and associated CVD despite the higher HDL concentrations.

In the end while in general statins have been impressive at controlling high cholesterol and its associated detrimental side effects to health, it is always wise to have alternative strategies. The best sought alternative to statins is a pharmaceutical agent that increases HDL(-C) concentrations due to their positive relationship with quality health outcomes to cholesterol related events. However, numerous studies have produced disappointing results for agents that increase HDL levels with regards to cholesterol related health outcomes, including the potential that more negative events become more probable. So what can be done about this issue?

Clearly if the above proposed theory regarding SR-BI as a limiting factor in the effectiveness of HDL is accurate then if one wants to raise HDL pharmaceutically to produce some form of health benefit, one must also increase SR-BI expression to properly manage the increased HDL and cholesterol associate concentrations. This process on its face should not be difficult as there are already existing pharmaceutical agents as well as natural agents that appear to increase SR-BI expression, but will demand proper study to identify its viability and safety over the long-term.


Citations –


1. Koyama, T, et Al. “Genetic variants of SLC17A1 are associated with cholesterol homeostasis and hyperhomocysteinaemia in Japanese men.” Nature: Scientific Reports. 2015. 5:15888-15899.

2. Arsenault, B, Boekholdt, S, and Kastelein, J. “Lipid parameters for measuring risk of cardiovascular disease.” Nat. Rev. Cardiol. 2011. 8:197-206.

3. Lewis, G, and Rader, D. “New insights into the regulation of HDL metabolism and reverse cholesterol transport.” Circ. Res. 2005. 96:1221-1232.

4. Rader, D. “Molecular regulation of HDL metabolism and function: implications for novel therapies.” The Journal of Clinical Investigation. 2006. 116(12):3090-3100.

5. Miller, G, and Miller, N. “Plasma-high ensity-lipoprotein concentration and development of ischaemic heart disease.” Lance. 1975. 1:16-19.

6. Goff, D, Jr, et Al. “2013 ACC/AGA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014. 129(2):S49-S73.

7. Kannel, W. “Lipids, diabetes, and coronary heart disease: insights from the Framingham Study.” Am. Heart J. 1985. 110:1100–1107.

8. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary of the third report of the National Cholesterol Education Program (NCEP). JAMA. 2001. 285:2486–2497.

9. Ross, R, and Glomset, J. “Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science. 1973, 180:1332–1339.

10. Barter, P, et Al. “Anti-inflammatory properties of HDL.” Circ. Res. 2004. 95:764-772.

11. Mineo, C, et Al. “Endothelial and anti-thrombotic actions of HDL.” Circ. Res. 2006. 98:1352-1364.

12. Agellon, L, et Al. “Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice.” J. Biol. Chem. 1991. 266. 10796-10801.

13. Tangirala, R, Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice.” Circulation. 1999. 100:1816-1822.

14. Mooradian, A, Haas, M, and Wong, N. “Transcriptional control of apolipoprotein A-I gene expression in diabetes.” Diabetes. 2004. 53:513-520.

15. Carlson, L. “Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review.” J. Intern. Med. 2005. 258:94–114.

16. Meyers, C, Kamanna, V, and Kashyap, M. “Niacin therapy in atherosclerosis.” Curr. Opin. Lipidol. 2004. 15:659–665.

17. Tunaru, S, et Al. “PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect.” Nat. Med. 2003. 9:352–355

18. Kuivenhoven, J, et Al. “The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J. Lipid Res. 1997. 38:191–205.

19. Ng, D. “Insight into the role of LCAT from mouse models.” Rev. Endocr. Metab. Disord. 2004. 5:311–318.

20. Schwartz, C, VandenBroek, J, and Cooper, P. “Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J. Lipid Res. 2004. 45:1594–1607.

21. De Grooth, G, et Al. “A review of CETP and its relation to atherosclerosis.” J. Lipid Res. 2004. 45:1967–1974.

22. Kuivenhoven, J, et Al. “Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia.” Am. J. Cardiol. 2005. 95:1085–1088.

23. Clark, R, et Al. “Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib.” Arterioscler. Thromb. Vasc. Biol. 2004. 24:490–497.

24. Boekholdt, S, et Al. “Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk population study.” Circulation. 2004. 110:1418–1423.

25. Rader, D, and Tall, A. “The not-so-simple HDL story: Is it time to revise the HDL cholesterol hypothesis?.” Nature medicine. 2012. 18(9):1344-1346.

26. Zanoni, P. “Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.” Science. 2016. 351(6278):1166-1171.

27. Haase, C, et Al. “LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals.” The Journal of Clinical Endocrinology & Metabolism. 2011. 97(2):E248-E256.

28. Wang, N, et Al. “Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein ApoB, low density lipoprotein ApoB, and high density lipoprotein in transgenic mice.” Journal of Biological Chemistry. 1998. 273(49):32920-32926.

29. Ueda, Y, et Al. “Lower plasma levels and accelerated clearance of high density lipoprotein (HDL) and non-HDL cholesterol in scavenger receptor class B type I transgenic mice.” Journal of Biological Chemistry. 1999 274(11):7165-7171.

30. Varban, M.L, et Al. “Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol.” PNAS 1998. 95(8):4619-4624.

31. Brundert, M, et Al. “Scavenger Receptor Class B Type I Mediates the Selective Uptake of High-Density Lipoprotein–Associated Cholesteryl Ester by the Liver in Mice.” Arteriosclerosis, thrombosis, and vascular biology. 2005. 25:143-148.

32. Acton, S, et Al. “Identification of scavenger receptor SR-BI as a high density lipoprotein receptor.” Science. 1996. 271(5248):518-520.

33. Silver, D, et Al. “High density lipoprotein (HDL) particle uptake mediated by scavenger receptor class B type 1 results in selective sorting of HDL cholesterol from protein and polarized cholesterol secretion.” J. Biol. Chem. 2001. 276:25287–25293.

34. Zhang, Y, et Al. “Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo.” J. Clin. Invest. 2005. 115:2870–2874. doi:10.1172/JCI25327.

35. Rothblat, G, et Al. “Cell cholesterol efflux: integration of old and new observations provides new insights.” J. Lipid Res. 1999. 40:781–796.

Looking for the Truth Behind the Health Value of Saturated Fat versus Carbohydrates

One of the more dynamic areas of modern research is nutrition and how it relates to biology. While in the past the more popular medium of discussion was through various diet/weight loss books, now the question of saturated fats and their overall influence on health has shifted to areas of more stringent study. Through most of the modern age of nutrition it has been viewed by the majority that saturated fats were largely negative and should be avoided as much as possible. Even the USDA recommends less than 10% of calories be derived from saturated fats1,2 largely based on the premise that increasing saturated fat consumption increases detrimental health outcomes including cardiovascular heart disease (CHD).3-5 However, there are individuals that believe this recommendation is inappropriate for it has not been clearly demonstrated empirically that increased consumption of saturated fat increases CHD or other negative health outcomes.

In fact some cite that while increasing saturated fat does increase total cholesterol, which is a characteristic for an increased rate of CHD, the rate of increase for high density lipoprotein (HDL) exceeds the rate of increase for low density lipoprotein (LDL), thus increasing the HDL/LDL ratio which is thought to be a more important factor to overall health than total cholesterol.6 Therefore, in the eyes of these individuals increasing saturated fatty acid (SFA) consumption in an equal caloric substitution over other types of nutrients like carbohydrates does not increase CHD risk and may even lower it.7-10 Overall the problem with both positions regarding the health effects of saturated fat is that most analysis fails to appreciate the specificity that addressing such an issue demands.

The crux of the question does involve the level at which one consumes saturated fats, but there are four central questions that govern the importance of that change:

First, different individual SFAs do not have the same biological effects despite similar molecular constructs. For example some epidemiological evidence demonstrates that stearic acid is the most detrimental SFA in terms of increasing the probability of CHD.11 Also despite the difficulty distinguishing between the overall effects of different SFAs palmitic acid is thought to be more detrimental to overall health than lauric acid. Not surprisingly in overall cholesterol raising effects stearic acid is neutral while all other long-chain acids increase both HDL and LDL levels versus low quality carbohydrates.12 There are no definitive conclusions regarding the influence of short and medium-chain SFAs due to a lack of study.

One of the reasons stearic and palmitic acid are so bad is that they can provide a negative feedback on acetyl-CoA carboxylase (ACC), the enzyme responsible for the catalysis of acetyl-CoA to malonyl-CoA which is utilized to increase the size of acyl chains reducing palmitic acid processing.13 In some respects there is little difference between trans-fatty acids and these two SFAs.

One would anticipate that it would be difficult to separate different types of SFAs with respect to what foods an individual consumes due to the combination of various SFAs in foods. However, it is feasible to distinguish certain specific foods that have higher percentages of certain SFAs over others and make broad dietary suggestions about those food items. For example palm oil and coconut oil have very high in palmitic and lauric acid concentrations respectively. Therefore, when studying the difference between SFAs and carbohydrates it is important to track what foods are consumed to ensure objectivity regarding certain SFA specific overload foods.

Second, when changing the amount of consumed SFAs some other molecule will replace those calories, thus it is important to consider the nature of that replacement and its specificity. Of the four issues that will be discussed this issue of substitution is the most studied one. There are a wide variety of elements that can replace saturated fat in a diet: protein, poly-unsaturated fat, mono-unsaturated fat, high glycemic index (low-quality/processed) carbohydrates, low glycemic index (high-quality) carbohydrates, “normal”/unsaturated fat and trans fats. Preliminary studies support the belief that rates of CHD decrease when replacing SFAs with poly-unsaturated fat, mono-unsaturated fat and “normal” fat.3,14,15 CHD rates increase when replacing SFAs with trans fats and refined/processed carbohydrates.3,16 Note that the glycemic index is utilized to measure how quickly blood sugar rise after consuming a given food and uses glucose as a upper level (100).

However, with regards to the carbohydrates since a large number of the carbohydrates that are consumed in modern society are of high glycemic variety if one were to guess it stands to reason that most, if not all, carbohydrate studies involved processed carbohydrates instead of quality carbohydrates. For example some proponents of SFAs like to cite studies that conclude a switch from SFAS to carbohydrates increases CHD probability. However, these studies do not typically differentiate between carbohydrate types. There is a large biological difference between low glycemic and high glycemic carbohydrates; without differentiating between carbohydrates any results born from substituting SFAs with a caloric equivalent amount of carbohydrates are inherently suspect. Think of it this way anyone who concludes that there is no biological and nutritional difference between consuming 150 calories of traditional rolled oats oatmeal versus 150 calories of Twinkie should not have their opinion taken into consideration.

In addition substitution studies must take appropriate caloric equivalency into account. For example if SFAs makes up 300 calories of a person’s daily caloric intake suitable comparison would demand that some percentage of that value be replaced with an equal value of the replacement (carbohydrates, poly unsaturated fat, etc.). It is sometimes difficult to track this equivalency feature if individuals are simply trying to recall what they consume over a given period of time versus keeping a food diary and having nutritionists correct for imbalances. Finally there is almost no information pertaining to replacing SFAs with protein or low glycemic index carbohydrates with regards to influence on CHD rates further limiting the value of substitution studies, an important exclusion that must be corrected for a definitive statement can be made regarding substitution. In the current environment the burden of proof is on those that believe SFAs are neutral or even better for health than processed carbohydrates, thus they need to ensure the quality of these substitution studies if they want to make the above contention.

Third, one of the biggest problems with comparing health effects between consumption of different food elements is a lack of comparison between subject microbiota. In short the microbiota is the concentration and type of bacteria population in an individual’s gastro-intestinal system. Numerous studies have demonstrated that the type of bacteria in an individual’s intestinal system have a significant impact on the ability to process and absorb nutrients.17-21 One of the biggest comparisons in microbiota is between Firmicutes and Bacteroidetes, which generally identifies obese individuals and non-obese individuals where Firmicutes is at larger concentrations in the obese and Bacteroidetes is at larger concentrations in the non-obese, usually with a 100%+ change.17,18 Note that this relationship is obviously not perfect, but is generally a good rule of thumb.

Evidence has shown that prolonged high SFAs feeding induced inflammation, impaired barrier function and changed microbiota profiles.22 The change in profiles lead to increased concentrations of Firmicutes and Oscillibacter and reduced concentrations of Bacteroidetes and Lactobacillus, thus high SFA feedings change the microbiota to one more seen in obese individuals. Clearly obesity is known for numerous detrimental health conditions, thus possessing a similar microbiota can be rationally viewed as a detrimental outcome versus a beneficial one.

Gut microbiota is important relative to carbohydrate processing as well in the rates and what types of carbohydrates are digestible.23,24 Fermentation occurring in the gut also leads to an increase in GLP-1 synthesis and insulin metabolism, thus rats fed a high fiber diet have higher plasma GLP-1, insulin and c-peptide levels after an oral glucose load.17 Various bacteria breakdown carbohydrates in fermentation reactions producing short chain fatty acids (SCFAs) like acetate, propionate and butyrate.25 Butyrate largely provides energy for colonic epithelia, propionate is taken up by the liver and is a precursor for gluconeogenesis, protein synthesis and liponeogenesis26,27 and acetate is metabolized by peripheral tissues and used as a substrate for cholesterol synthesis.28

The ratio of which SCFAs are produced is largely dependent on the ratio of bacteria in the gut. Evidence suggests that Firmicutes is able to produce about 25% more SCFAs than Bacteroidetes.19,20 Firmicutes appears to produce more butyrate and propionate with Bacteroidetes producing more acetate.29 There is question whether or not higher amounts of SCFAs are linked to obesity, but the evidence favors the affirmative: that increased SCFAs increase obesity probability.18,21,30 Also Firmicutes may increase the rate of malonyl-CoA activation over Bacteroidetes, which reduces the rate of carnitine palmitoyl transferase-1 reducing the amount of mitochondrial fatty acid oxidation.31 Overall while there is still a lot of information that needs to be deduced from the relationship between microbiota and health in general, especially obesity, the exclusion of any relationship in substitution studies is inappropriate.

Fourth, with regards to carbohydrate substitution, physical and aerobic conditioning of the research subject must be taken into consideration. Consistent exercise results in the increased direct and indirect consumption of carbohydrates as an energy source. Indirect consumption occurs through the increased production of specific enzymes, which favor the conversion of certain carbohydrates to glycogen versus SFAs like stearic or palmitic acid. Basically if one is substituting carbohydrates for SFAs in overweight and/or inactive research subjects the biological reduction of SFA consumption is heavily handicapped because the substituted carbohydrates are less likely to be used as short-term energy, but instead are converted to SFAs for long term energy storage.

One of the important elements when distinguishing between biological effects of SFAs and carbohydrates is the synthesis and consumption of glycogen. Glycogen is a multi-branched polysaccharide consisting of various glucose derivative molecules bound together and is used for long-term energy storage in a more compact form over triglycerides.

Glycogen is principally isolated within muscles, the liver and red blood cells32,33 and its rate of storage is dependant on physical training, basal metabolic rate and eating habits. Storage begins when blood glucose levels rise and insulin concentrations increase stimulating the action of hepatocytes leading to glycogen synthesis. As long as glucose and insulin remain in high relative concentrations glycogen synthesis continues. In periods of low glucose the pancreas secretes glucagons which catalyzes glycogenolysis.

Not surprisingly glycogen synthesis is exogonic, where UTP reacting with glucose-1-phosphate to drive the formation of UDP-glucose that eventually combine to lengthen glycogen through catalyzation by glycogen synthase forming from a base created by glycogenin.33 Glycogen consumption is endergonic where sections are cleaved by glycogen phosphorylase to produce glucose-1-phosphate monomers, which are later converted to glucose-6-phosphate by phosphoglucomutase. Glucose-6-phosphate produced from glycogen can enter the glycolysis pathway, the pentose phosphate pathway or be dephosphorylated back to glucose.33

A history of exercise, especially endurance training, enhances lipid and carbohydrate oxidation and decrease SNS activity during present time exercising in part due to increased muscle glycogenolysis and increased recruitment of skeletal muscle.34-38 Increasing exercise intensity increases the level of energy demand from the muscles and brain resulting in a faster crossover from lipids to carbohydrates as a source of energy. While some believe that there are special exercise-dietary regimens to enhance muscle glycogen storage/consumption rates when appropriate, there is no doubt that individuals who exercise consistently have higher rates of glycogen conversion of glucose and other sugars versus rates of glucose conversion to SFAs opposed to the rates found in overweight or obese individuals.34,39,40

One of the advantages of this difference is in the short period of time after exercise (24 hrs) is that rate of glycogen synthesis is indiscriminate the type of carbohydrate, be it simple or complex.40 Note that there is still an insulin concentration rise for simple carbohydrates over complex, but while the increase for complex is smaller the duration is longer.40 The fate of consumed carbohydrates is also influenced by the time between consumption and exercise.41 Therefore, individuals that are “in shape” are more likely to burn off consumed carbohydrates versus storing them as either glycogen or SFAs. Again comparison studies between SFAs and substitutions, especially carbohydrates, tend to exclude the influence of exercise.

Another side issue that must be considered when making comparison studies between SFAs and substitutes is the concentration of epinephrine due to its lipolytic, glycogenolytic and insulin-suppressive effects.42 Past training through exercise seems to reduce epinephrine concentrations in both at rest and during present exercise.42,43 Therefore, measurement of epinephrine needs to be conducted to act as a control point to make more accurate comparisons in substitution studies.

Overall there are clearly scientific and accuracy concerns regarding claims made by individuals who believe that SFAs are no more harmful to CHD rates than carbohydrates. Unfortunately such claims are typically made by individuals who are trying to justify a certain nutritional lifestyle versus individuals who actually care about proper nutrition. This is not to say that all forms of carbohydrates are guaranteed to be healthier than SFAs; the problem is that SFAs proponents have not produced evidence to demonstrate this conclusion that satisfies the four above concerns. Therefore, until this evidence is produced it is irresponsible of individuals to suggest that substituting SFAs for carbohydrates produces no detrimental change to CHD rates.


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Citations –

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