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Sunday, August 28, 2011

Where do triglycerides come from? Part III

If you haven't done so already, you may want to read Part I and Part II first.  Part II, especially, discusses the sources of fatty acids for VLDL triglycerides manufactured by the liver and two secretory pathways - an immediate one and a delayed one.  In this part I'll discuss the results of that study:



This group uses different radioactive tracers to identify the source the fatty acids in VLDL-triglycerides.  This study differed from the study in Part I in that it looked at prolonged triglyceride levels - fasting and postprandial - rather than just fasting.  For one week prior to the study all subjects were provided a standard diet (outpatient basis) of 50% carb, 35% fat, 15% protein*, at weight maintaining levels.  I would note that this would mean the obese study groups were likely ingesting significantly more than the lean controls.  The study diet followed for 5 weeks essentially replaced 20% of fat energy with carbohydrate energy for approximately 70% carb, 15% fat, 15% protein*.    It was noted that caloric content was similar, simple sugars were the same as a percentage, but absolute simple sugar intake was almost 40% more on the high carb diet.  The high carb diet also contained 50% more fiber and almost 90% less cholesterol.

(*) The numbers in the table do not quite add up so I'm giving rounded approximates.

The two study group subjects were all hypertriglyceridemic obese, one was non-diabetic and the other with diagnosed diabetics.  The control group was lean.

This is a somewhat small study (18 total) participants in 3 groups of 6.  Two of the groups were mixed gender  which might be of interest in the results for clearance of triglycerides as we've seen that there are differences (generally longer in males).  I'll give the M/F ratio for the groups.  I also question why the control group was considerably younger on average than the other groups and provide that info as well.  All descriptives are approximate average
  • Control (C):  M/F = 4/2, Age 27, Lean (74 kg, 24 BMI),  fasting triglycerides <100
  • Hypertriglyceridemic Non-diabetic (HPTG in paper, I'll use HN):  M/F = 6/0, Age 49, Obese (93 kg, 31 BMI), fasting triglycerides 150-300.
  • Hypertriglyceridemic Diabetic (DM HPTG in paper, I'll use HD):  M/F = 4/2, Age 52, Obese (103 kg, 35 BMI), fasting triglycerides 150-300.
Summary of Results on the LF/HC diet:
  • Fasting triglycerides increased by 60% in all subjects 
  • Transport rate of VLDL-TG was not increased 
  • The half-life of VLDL-TG was prolonged
  • Clearance of VLDL-TG was significantly reduced
  • Fasting apo B-48 concentrations were elevated
  • De novo lipogenesis was not increased
Excerpts:
... These underscore the ability of LF/HC diets to elevate fasting plasma TG even when the diet is composed of whole foods and is low in simple sugars. Increased secretion of TG was not the primary kinetic mechanism responsible for this carbohydrate-induced TG elevation, however; reduced TG clearance from the plasma was the major metabolic mechanism involved. This conclusion reveals a difference in the underlying mechanism from hypertriglyceridemia observed on higher-fat diets. ...
... . In the present study, the TG secretion rate of HTG subjects was 2.7-fold higher than that of the NL subjects on the higher-fat diet.  In contrast, carbohydrate-induced elevations in TG were explained by reduced clearance of VLDL-TG rather than increased production. ...

So I'll repost the graphic w/o explanation VLDL-TG sources from the paper (see discussion in Part II):


Here were the results for the fasting VLDL:



Summary of Source of VLDL Triglycerides on Control Diet
  • NEFA provided only 84% of fatty acids in HT subjects vs. more than 93% in normal controls.
  • DNL  accounted for less than 5% in both groups 
  • Roughly 13% of triglycerides are not accounted for by either NEFA or DNL in the HT subjects 
Sources of Triglycerides on Low Carb/High Fat diet


Comparing just the normoglycemic groups (Control & HN) on study diet
  • The proportion of fatty acids from NEFA were reduced considerably in both groups to 79% (64% immediate + 15% delayed)  for normal controls and only 53% (33% immediate + 20% delayed) in HN.
  • The proportion from DNL was essentially unchanged in controls, but did increase considerably in HN to 14%, still this wasn't the significant factor in the increased fasting VLDL
  • The fatty acids unaccounted for by NEFA or DNL in HN group more than doubled to 29%
The authors go on to speculate as to the source of the fatty acids.  They seem to rule out both hepatic stores (fatty liver), because of the 24 hr fast for the infusion test then employed, and visceral fat, because they observed no change in body composition on the high carb diet so this would not explain the increase from this source.  I'm not so sure about the visceral fat as the VLDL is still not a whole lot mass-wise -- to me it is conceivable that a high carb low fat diet could "activate" the metabolically active visceral fat.

Nonetheless, a source they describe as "interesting" seems to be their favored one:  chylomicron remnants.
In rats, chylomicron remnants contain approximately 50% of their original TG when cleared to the liver.  Very little is known about this process in humans. The 2-fold elevation in fasting apo B-48 concentrations observed in the HTG subjects after the LF/HC diet suggests that chylomicron remnants might provide a significant source of VLDL-TG fatty acids in the fasting state. The increased presence of B-48–containing TG-rich lipoproteins was surprising, given that the blood draw for this measurement occurred after the subjects had fasted 15 hours and that the last meal they consumed contained very little fat (15% of energy). However, Karpe et al. have shown that the chylomicron remnant pool contains lipoprotein populations that are heterogeneous. One population may have a very short half-life (<15 minutes), whereas others may circulate for much longer periods. The elevation in fasting apo B-48 associated with LF/HC feeding could have resulted from alterations in the intestinal secretion pattern of chylomicrons, such that more particles were secreted in the fasting state or that a subpopulation of the chylomicrons secreted postprandially circulated for a longer time. This result requires further investigation.

Speculation:  
What follows in this paragraph is purely speculation on my part, so I want to state that up front rather than having to use wishy washy terms to clutter the wording.  So I will use definitive words, but they should be taken as supposition and nothing more!
I think the chylo remnants are a very plausible source for the missing fatty acids in VLDL triglycerides.  On a low fat diet, one would expect fewer chylomicrons to begin with, and fewer leftovers.  Although insulin does stimulate fatty acid uptake/esterification into adipose tissue, ASP seems to play a more critical role with high fat meals with lots of chylo.  Adipocytes via ASP preferentially take up chylomicrons compared to VLDL apparently mediated by different surface signaling proteins favoring chylo uptake. It is also conceivable  that just as VLC diets mimic a gluco-fasted state due to low dietary carb, a VLF diet could mimic a lipo-fasted state.  If this is the case, it's been shown that more chylo are broken down by LPL for uptake and use by peripheral tissues in the fasted state, while considerably more go straight to adipose tissue in the fed state.  These two factors combined (lesser stimulation of chylo uptake by ASP and greater utilization of chylo for immediate energy needs) would be consistent with generating more chylomicron remnants -- which are exactly what their term implies -- the remnants of chylomicrons.  That these would circulate around for longer makes absolute sense to me.     { / speculation }

In the present study, sources other than NEFA and de novo lipogenesis contributed significantly to VLDL-TG assembly in HTG subjects, and these sources contributed even more when HTG subjects consumed the LF/HC diet. The assembly, production, and clearance of elevated plasma VLDL-TG in response to the LF/HC diet differed from that associated with the elevated TG on the higher-fat diet.
I'm disappointed that they did not address the >100% "accounted for" in the diabetic HTG group.  Indeed they didn't make much of the differing results between the HTG groups at all.   As for DNL, from the discussion:
The fractional contributions from DNL to fasting VLDL-TG via the delayed secretory pathway were 3 ± 0.3%, 14 ± 3%, and 13 ± 4% in the control, HPTG, and diabetic HPTG groups, respectively.  Estimated absolute contributions were 0.3 ± 0.03, 4.5 ± 1.2, and 2.8 ± 0.8 g/day. The absolute contribution was significantly higher in the HPTG and diabetic HPTG groups compared with the control group (P < 0.011). The fractional contribution from DNL was highly variable in the diabetic HPTG group, although consistent within each individual, and ranged from 3% to 25%. It was not possible to identify any clinical or metabolic variables that correlated with the differences in lipogenesis among the diabetic HPTG subjects.



So ... a couple of running themes here at the Asylum as regards oft repeated myths in the LC community:
  1. A high carb diet does not, via de novo lipogenesis, even in the obese and diabetic, contribute greatly to VLDL triglycerides secreted by the liver.
  2. The contribution to VLDL from DNL -- aka converting carbs to fat -- is only a matter of a several grams per day even in the worst cases.
  3. It seems that high carb low fat diets seem to interfere with or somehow slow take-up of dietary fat into adipose tissue rather than the "hoarding" proposed.

3 comments:

Ned Kock said...

Hi CS. Fasting TG levels are highly correlated with VLDL-C, which suggests that DNL is the key to increased fasting TG in HC diets. In many HCE (software) users, I see correlations of 0.99 or so between fasting TG levels and VLDL-C.

Evelyn aka CarbSane said...

Hi Ned, I've always been confused about this, but essentially my understanding is that for all intent and purposes, in the fasted state VLDL = triglycerides.

One cite: Because VLDL carry most of the triglyceride in plasma, the VLDL triglyceride and plasma triglyceride levels are almost the same (there is a bit of triglyceride in low-density lipoprotein and high-density lipoprotein) during fasting.

This study (and the prior one from the same group in part I if I'm not mistaken) seem to essentially treat them as synonymous, and your HCE users getting 0.99 correlations would support this. NEFA is by far the greatest contributor of fatty acids on all diets, but these tracer studies demonstrate that increased DNL cannot explain the increased fasting triglycerides.

Lerner said...

In looking at what really matters in health, which are actual outcomes studies, there is the following from ESC 2011 in Paris this week - concerning the "Homburg Cream and Sugar" study and triglycerides, especially postprandial TAG.

From clinicaltrials.gov, the study purpose is "to prospectivly analyze the correlation of triglyceride tolerance and glucose tolerance with cardiovascular morbidity and mortality in patients with stable coronary artery disease within 18 months and to determine, whether measurement of triglyceride tolerance can discriminate patients at risk for cardiovascular events."


The article, also containing a nice video interview with the lead author, is at:
http://www.theheart.org/article/1269389.do

The study "examined—for the first time—metabolic status together with postprandial triglyceride levels to see whether the latter predicted cardiovascular events; investigators found that, in the overall study population, they did not."

BUT

"In those with normal glucose tolerance, the hazard ratio for the primary end point was 3.10 (p=0.04) for those in the highest tertile of fasting triglycerides (compared with lowest), and 4.45 (p=0.02) for those in the highest tertile of postprandial triglycerides."

So, the big news is that outcomes are different in normal versus impaired secondary PTs - and so lowering of TAG could be of benefit in normals but not impaireds. And maybe that also applies in primary prevention.

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