Plasma cholesterol is derived from two sources:
- exogenous (dietary and biliary excretion)
- endogenous (liver and peripheral tissues)
Exogenous
Dietary and biliary cholesterol are absorbed in the intestine by a saturable transport mechanism.
Roughly 2/3 of intestinal cholesterol is from bile and 1/3 from diet.
Diet cholesterol absorption ( percentage of the intake ) is very different from people to people and it has a Gaussian distribution, ranging from almost null to 100% on a genetic base whith an average intake (around 400 mg/d).
Roughly 50% f intestinal cholesterol is absorbed and recycled while the remaining part is eliminated with feces.
Importantly, individual variability exists with regard to the proportion of cholesterol that is absorbed or synthesized, depending on sensitivity of HMG-CoA reductase to inhibition by exogenous cholesterol. (Physiological and therapeutic factors affecting cholesterol metabolism: does a reciprocal relationship between cholesterol absorption and synthesis really exist? )
Evaluation of the relative role of cholesterol absorption or synthesis in determining its serum level is difficult even using radioactive tracer. Therefore in most studies the ratio between cholestanol/cholesterol and fitosterols/cholesterol is used as indirect marker of these fluxes.
This kind of measurements is affected by large incertainities and therefore appliable only to very large samples.
New insights into the regulation of HDL metabolism and reverse cholesterol transport.2005
Cholestanol: A serum marker to guide LDL cholesterol-lowering therapy
The interaction of cholesterol absorption and cholesterol synthesis in man
Effects of dietary cholesterol on the regulation of total body cholesterol in man
The number of receptors involved in intestinal cholesterol uptake explains the variability and umpredictability of the process
Daily synthesis in healthy man is around 750/1000 mg cholesterol (ca 2/3 of daily requirement), with an intake of around 250/400 mg. But increased dietary intake can reduce the net synthesis
Cholesterol synthesis takes place in both liver (around 20%) and other peripheral tissues (mainly gut) and it strongly dependent on intestinal uptake as de novo cholesterol synthesis is inhibited at the level of HMG-CoA reductase by exogenous cholesterol. (Diurnal and dietary-induced changes in cholesterol synthesis correlate with levels of mRNA for HMG-CoA reductase)
Circadian rythm of cholesterol synthesis
Evidence for diurnal periodicity in human cholesterol synthesis
Cholesterol efflux from the cell
The cholesterol efflux from the cell is mediated by a carrier called ABCA1 belonging to the family of ABC transporter
Cholesterol transport
LuXuRies of Lipid Homeostasis: The Unity of Nuclear Hormone Receptors, Transcription Regulation, and Cholesterol Sensing 2009
Regulation of ABC1 activity
The ABC1 belongs to the family of the ABC-transporter including also the MDR1/pgp
Cerebral vascular dysfunction during hypercholesterolemia.
Metabolic and Hormonal regulation of Cholesterol Metabolism
The stringent regulation of the different metabolic pathways is achieved through a set of interactions including nutrients concentration, hormones and Nuclear Factors, leading to a tight dependence from any environmental change (diet, fasting, etc).
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See Cartoon
Role of intestinal sterol transporters Abcg5, Abcg8, and Npc1l1 in cholesterol absorption in mice: gender and age effects. 2006
Glucose and Insulin release
Insulin effects
Regulation of cholesterol metabolism by Nuclear Factors
Sterol response element binding protein (SREBP)-2 and SREBP-1c at the branching point of cholesterol and fatty acid metabolism
The coordinated action of FXR, LXR, and SREBP-2 in the cholesterol metabolism
The major source of cholesterol is the diet, while de novo synthesis of cholesterol is stimulated by SREBP-2 if supplies are too low. If cholesterol is in excess, its efflux from the cells and its conversion into bile acids for excretion in the feces are favored by the activation of liver X receptor (LXR). High bile acid production in turn activates farnesol X receptor (FXR), which limits the toxic accumulation of these metabolites in the liver, by increasing their cell efflux and limiting their production. The plain blue arrows correspond to the action of these transcription factors on the genes acting in the cholesterol metabolic pathway. The gray arrows correspond to the action of these gene products. Some bile acid and cholesterol metabolites are ligands for FXR and LXR, respectively (blue dotted line), while high cholesterol levels directly inhibit SREBP-2.
Metabolic adjustment of glucose metabolism upon fasting.
Summary of the network established by the transcription factors involved in metabolic regulation
Summary of the network established by the transcription factors involved in metabolic regulation. Each of the transcription factors mentioned in this figure participates in the regulation of at least one aspect of metabolism, often by sensing metabolite levels and adapting the cell response through transcriptional regulation of enzymes belonging to different pathways. In addition, each of them may influence the activity of the others, creating a regulatory network
by which homeostasis is achieved.
Thyroid hormones and cholesterol
Hypothyroidism is associated with hypercholesterolemia and hyperthyroidism with hypocholesterolemia
Thyroid hormone has a stimulatory effect on HMGCoA-reductase increasing de novo cholesterol synthesis, but has an inhibitory effect on cholesterol absorption
Which is the molecular mechanism?
Shin DJ et al propose that the decreased LDL receptor and increased serum cholesterol associated with hypothyroidism are secondary to the thyroid hormone effects on SREBP-2. These results suggest that hypercholesterolemia associated with hypothyroidism can be reversed by agents that directly increase SREBP-2. Additionally, these results indicate that mutations or drugs that lower nuclear SREBP-2 would cause hypercholesterolemia. (Thyroid hormone regulation and cholesterol metabolism are connected through Sterol Regulatory Element-Binding Protein-2 (SREBP-2).)
The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study. 2007
