CR and cholesterol production

[Guest guest]

CRers appear to stop endogenous production of cholesterol effectively. It was

interesting to present the results for Figure 2 comparing CR with other means of

blood cholesterol reduction in humans. It is food for not thought?

PJ.

Regulation of cholesterol biosynthesis by diet in humans.

Am J Clin Nutr. 1997 Aug;66(2):438-46. Review.

PMID: 9250128 http://tinyurl.com/mjwoy

... Dietary factors influencing human cholesterol synthesis include energy

restriction, meal frequency, dietary fat type, and cholesterol and phytosterol

content. Food deprivation for as short as 24 h results in almost complete

cessation

of cholesterol biosynthesis. Similarly, increased meal frequency patterns are

associated with a substantial depression in synthesis. In contrast, consumption

of

oils rich in polyunsaturated fatty acids, despite reducing circulating

concentrations, increases the cholesterol synthesis rate compared with other

fats.

Stepwise addition of dietary cholesterol is associated with only a modest

decline in

cholesterogenesis while raising plasma concentrations slightly. It can be

concluded

that synthesis, as a contributor to circulating cholesterol concentrations, is

sensitive to many dietary factors. Energy deprivation results in the greatest

decline in synthesis, likely accounting for the beneficial decline in

circulating

cholesterol concentrations observed with weight loss.

... Food deprivation might be anticipated to exert two possible actions on

cholesterol synthesis. First, if dietary cholesterol was an important control

element, desuppression of cholesterogenesis would occur through removal of

incoming

dietary input. Second, and in contrast, synthesis inhibition would be expected

if

interruption of substrate supply for cholesterogenesis was an important

regulatory

factor. Both animal and human literature bear out that any desuppression due to

absence of dietary cholesterol during food deprivation is minor compared with

the

suppression caused by the removal of energy input itself. It has been

established

that food restriction results in a marked reduction of cholesterogenesis in

animals

(50, 54) and moderate suppression (59-61) to almost complete suppression (43,

52) in

human subjects. Although correlations between excess body weight and synthesis

rates

have been identified (59, 60), suggesting that synthesis reequilibrates to a new

lower level with weight loss, it has also been shown that even very acute energy

restriction without weight loss exerts an immediate suppression of synthesis

(43,

61). Food restriction may result in a decrease in available precursor for

pathways

of lipogenesis (50, 55). These observations provide an explanation for the

reduction

in circulating cholesterol concentrations seen with weight loss in humans in

negative energy balance situations. Presumably, as with fatty acid synthesis, an

adequate supply of carbon atoms fluxing through the acetyl CoA pool is required

for

the cholesterol synthetic process. The action of dietary restriction on sterol

biosynthesis is the most dramatic of any dietary perturbations observed thus far

in

humans.

Meal frequency ... The possible beneficial action of increasing the number

of

meals consumed each day has been examined from several standpoints. Reduced

circulatory concentrations of total and low-density-lipoprotein (LDL)

cholesterol

have been observed in individuals consuming the same amount of food as many

small

rather than as fewer large meals each day (62). Associated with these changes

were

lower circulating insulin concentrations, suggesting that insulin action may be

a

potent promoter of cholesterogenesis (62). Work in humans studying the actions

of

increased meal frequency on cholesterol synthesis reveal cholesterogenesis rates

about one-third less in subjects provided with meals every 4 h around the clock

compared with subjects given the same food as three meals per day at normal

mealtimes (53). Substantially reduced mean daily insulin and gastric inhibitory

polypeptide concentrations were observed in these nibblers, suggesting that

hormonal

actions are responsible for the reduced cholesterol synthesis observed (53).

Insulin

has been shown to stimulate the incorporation of labeled acetate into

cholesterol

(63) and LDL binding and degradation (64) in vitro. Insulin may also work

indirectly

because the activities of other enzymes associated with the cholesterogenesis

pathway, pyruvate dehydrogenase and phosphofructokinase, are insulin dependent

(65).

It can be speculated that both availability of carbon-source precursors and

favorable hormonal profiles are essential for cholesterogenesis to occur.

....

... The dietary factor producing the greatest change in synthesis in humans

is

food restriction. It can be speculated that both hepatic and extrahepatic

synthesis

declines because of the fall in circulating insulin concentrations, as is seen

with

consumption (if evenly spaced meals or food deprivation. A direct action of

diminished substrate availability may further suppress whole-body synthesis in

all

active tissues, accounting for the immediate and pronounced reduction seen with

food

deprivation. Here, the lack of available substrate appears to be a stronger

suppresser of synthesis than is the absence of exogenous, dietary cholesterol,

in

desuppressing synthesis. An important and yet unanswered question is at what

level

of food restriction does a substantial decline in cholesterogenesis, and

circulating

concentrations, occur. The type of dietary fat similarly influences

cholesterogenesis in liver and perhaps intestine through regulation of the free

sterol pool. Hepatic PUFA may result in esterification of free cholesterol from

cellular regulatory pools. The decline in free cholesterol concentrations

stimulates

the rate of sterol synthesis. The modest suppression of synthesis in the face of

increases in exogenous cholesterol reflects suppression of hepatic synthesis,

whereas extrahepatic synthesis remains relatively unaffected. Conversely, plant

sterols, particularly saturated sterols such as sitostanol, enhance hepatic

biosynthesis through reduction of the absorption of both exogenously and

endogenously derived intestinal cholesterol, and thus, hepatic cholesterol

delivery

via chylomicron remnants. Comparison of the response to various dietary factors

of

human cholesterogenesis ... is summarized in Figure 2.

Figure 2. Extent of action of dietary factors on organ cholesterol

biosynthesis

in adult humans.

======================

Diet factor Cholesterol biosynthesis

======================

Food Restriction -100%

Meal frequency -36%

MUFA -11%

PUFA +39%

Cholesterol (mg/day)

650 -20%

50 +15%

======================

MUFA. monounsaturated fatty acid: PUFA. polyunsaturated fatty acid.

... cholesterol biosynthesis rates in humans, the factor identified as

having

the strongest influence on synthesis is negative energy balance. Food

restriction

and weight loss have been shown to reduce both cholesterol plasma concentrations

and

synthesis. These findings underscore the importance of energy balance in the

control

of circulating cholesterol concentrations.

-- Al Pater, alpater@...

-- Al Pater, PhD; email: old542000@...

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