There has been considerable discussion in the past week regarding human
blood lipid responses to high and low carbohydrate diets and whether or
not there is a genetic basis for differential responders.   To follow up
on this discussion, I would like to point out that there is substantial
evidence to show that blood lipid response to variation in dietary fat
and cholesterol intake varies widely among individuals (1,2,3) and that
this variability is likely attributable to genetic factors with
polymorphisms at several genetic loci including genes for
apolipoproteins and for low density lipoprotein (LDL) particle size and
density (4).
        There is a LDL subclass called pattern "B" which is
characterized by a preponderance of small, dense LDL particles, elevated
triglycerides, low high density (HDL) cholesterol and increased coronary
heart disease (CHD) risk.   LDL pattern B occurs in ~30% of the male
population (5).   LDL subclass pattern "A" is characterized by larger
more buoyant LDL particles.   Low fat, high carbohydrate diets induce a
reduction in the atherogenic small dense LDL  in individuals displaying
pattern "B" and also cause reductions in LDL cholesterol that are
greater than in subjects displaying pattern "A" (6).  These data clearly
suggest that low fat, high carbohydrate diets may be more effective in
lowering  LDL cholesterol and small dense LDL in about 30% of the
population, and less effective in 70% of the population.
        LDL subclass pattern B is influenced by a major gene or genes
with a prevalence in the American population estimated to be 0.25 (5).
The specific gene or genes responsible for this trait have not been
identified, but there is evidence to show linkage to polymorphic markers
near the LDL receptor gene on chromosome 19p (7).
        To date, there are no experimental data evaluating the effects
of quite low carbohydrate diets (<30% of total energy) upon blood lipid
responses in LDL subclasses A or B, however Krauss et al. (8) have
clearly shown that all subjects (n=105) whether subclass A or B
responded to a high fat diet (46% energy) by  substantial increases in
LDL cholesterol and responded to a low fat diet (23.9% energy) by
decreases in LDL cholesterol.   This information  does not support
Dean's contention in a previous post that differential responders to
high and low fat diets bias interpretation of dietary intervention
trials, nor does it lend support to his proposal that high fat diets can
improve blood lipid profiles.    I contend that any improvement in total
cholesterol or LDL cholesterol by uncontrolled, self administered low
carbohydrate diets (such as followed by Dean and others) are an artifact
of (a) reductions in total caloric intake,(b) increases in total
protein, (c) unknowing changes in the dietary P:M:S ratio, (d)  and
combination of the three.   Further, improvements in TG, VLDL and HDL
can be mainly attributable to reductions in carbohydrate.   Under
isocalorically controlled conditions in which dietary saturated fat is
increased at the expense of any other lipid or macronutrient, there will
be a characteristic increase in LDL cholesterol as shown time and again
with meta analyses (9) under metabolic ward conditions (10) and
corroborated by in vitro and in vivo data showing that LDL receptors are
down regulated by dietary saturated fat (11).

                                Cordially,


                                Loren


                                REFERENCES

1.      Mistry F et al.  Individual variation in the effects of dietary
cholesterol on plasma lipoproteins and cellular homeostasis in man. J
Clin Invest 1981;67:493-502.
2.      Jacobs DR et al.  Variability in individual serum cholesterol
response to change in diet. Arteriosclerosis 1983;3
3.      Katan MB et al.  Congruence of individual responsiveness to
dietary cholesterol and to saturated fat in humans. J Lipid Res
1988;29:883-92.
4.      Dreon DM et al.  Gene-diet interactions in lipoprotein
metabolism. Monographs in Human Genetics 1992;14:325-49.
5.      Austin MA et al.  Inheritance of low-density lipoprotein
subclass patterns:results of complex segregation analysis.  Am J Hum
Genet 1988;43:838-46.
6.      Dreon DM, Krauss RM.  Diet-gene interactions in human
lipoprotein metabolism. J Am Coll Nutr 1997;16:313-24.
7.      Nishina PM et al.  Linkage of atherogenic lipoprotein phenotype
to the low density lipoprotein receptro locus on the short arm of
chromosome 19. Proc Natl Acad Sci 1992;89:708-12.
8.      Krauss RM, Dreon DM.  Low density-lipoprotein subclasses and
response to a low-fat diet in healthy men. Am J Clin Nutr
1995;62:478s-87s.
9.      Howell WH et al.  Plasma lipid and lipoprotein responses to
dietary fat and cholesterol: a meta analysis. Am J Clin Nutr
1997;65:1747-64.
10.     Phinney SD et al.  The human metabolic response to chronic
ketosis without caloric restriction: physical and biochemical
adaptation. Metabolism 1983;32:757-68.
11.     Brown MS, Goldstein JL.  Receptor mediated control of
cholesterol metabolism. Science 1976;191:150-4.