The dead loop of free fatty acids

V.V. Velkov, Candidate of Biological Sciences
CJSC "DEACON", 142290, Pushchino, Moscow region, Prospekt Nauki, 5

An abridged version of the article was published in the journal "Chemistry and Life – the 21st Century" No. 2-2009

A stupid penguin timidly hides a fat body in the cliffs... The time when he was hiding has passed. Now he doesn't hide it. Now everything is different.

Above the gray plain of the sea
A fat penguin proudly flies.
He no longer remembers himself,
How he was able to get up from the ground.

He doesn't remember – we will remind. From the cliffs, the fat penguin rose up along with the world obesity statistics.

Obesity statistics in different countries at the turn of the millennium
(according to the United Nations Organization for Economic Cooperation and Development).
Here and further, obesity is considered a body mass index exceeding 30.
It is calculated by the formula:
BMI = m/h ²,
where m is body weight in kilograms, h is height in meters.
In Russia at the beginning of the XXI century, according to various data, obesity occurs in 23-36% of adults.

And here is the "victorious tread" of obesity in England (data from the British Medical Research Council).

The risk of obesity depends on many factors (women are asked not to look).

Percentage of obese people, depending on the country of residence, gender and ethnicity
(according to the International Society of Nutritionists for the 1990s)

Everyone else is asked not to read further. Because obesity is the main cause of the plague of the 21st century, metabolic syndrome (MS). This is a complex of biochemical, hormonal and clinical pathologies leading to insulin resistance (IR), or type II diabetes mellitus, when insulin is produced in the body, but the cells are not sensitive to it (resistant). Glucose does not enter such cells and accumulates in the blood (hyperglycemia). Recall that in diabetes mellitus of the first type there is no or little active insulin in the body. Metabolic syndrome has five diagnostic signs, which are sometimes called the "deadly quintet":

• The ratio of waist and hip volumes: more than 0.8 for women and 1.0 for men;
• Blood pressure: equal to or greater than 130/85 mmHg.;
• Fasting blood glucose: equal to or greater than 6.1 mmol/l;
• Blood triglyceride level: equal to or more than 1.7 mmol/L;
• Reduction of high-density lipoprotein cholesterol (LDL-C): more than 1 mmol/l in men, more than 1.3 mmol/l in women.

A trio of any five "musicians" is enough to diagnose "metabolic syndrome". Pay attention to the fourth and fifth violins. What they play is called hyperlipidemia (an increase in triglyceride levels, a decrease in "good" HDL-C, an increase in "bad" cholesterol – low-density lipoproteins, LDL-C). The code of this quintet is ischemic heart disease (CHD), and the final is acute myocardial infarction (AMI) or ischemic stroke. And the "life-affirming" prelude was it. Fatness.

Obesity is a plague of the XXI century associated with low socio-economic status. It could be assumed that obesity most often occurs in people with a relatively high economic status, which allows excessive food intake. Alas. At least in industrial countries. Here are the facts. In the USA, a large-scale study (4,978 men and 2,035 women aged 39 to 63 years were examined) revealed an inverse relationship between a person's position on the socio-economic ladder and the likelihood of having a metabolic syndrome. Conclusion: the development of MS is a biological mechanism that leads to "social inequality" in the distribution of cardiovascular risks among people. And there is no justice here, so that everyone is equal. According to statistics, people with high socio-economic status have significantly lower such risks.

It seems that it is childhood spent in poverty that leads to obesity in adulthood. This was discovered when 4,774 men and 2,206 women born in 1930-1953 were studied. At first, it was found that high coronary risks (elevated triglyceride levels and low HDL-C levels) are more strongly associated with low socio-economic status already in adulthood than with "poor childhood". Later, however, it turned out that overweight in mature years was observed mainly in those people whose fathers belonged to lower social classes. It is believed that a low socioeconomic status begins to increase coronary risks starting from childhood, which sharply increase with a decrease in socioeconomic status in adulthood.

Smoking kills. Obesity too. In the USA, MS is present in 22.8% of men and 22.6% of women. At the same time, it is diagnosed in 4.6% of people with normal weight, in 22.4% of overweight people and in 59.6% of obese people.

Not up to fat – I would liveFats are triglycerides, complete esters of glycerol and monobasic fatty acids.

As it turned out, numerous pathologies associated with obesity are caused by elevated levels of free fatty acids (FFA) in the blood that are not associated with proteins (albumin). FFA is formed as a result of hydrolysis of triglycerides contained in adipose tissues. And the proverb "not up to fat, I would live" has nothing to do with reality. Even as "to fat"! After all, the FCS that are formed from it is one of our most important "fuel and energy resources". In the blood plasma, fatty acids are either esterified and mostly bound to albumin, or are not esterified and are in a free state. It is about them that we are talking. In plasma, free fatty acids are found in the concentration range from 100 micromol/l to 1 mmol/l and their level strongly depends on the time of day. After each daily meal, the level of FFA in plasma drops. Indeed, if we have just eaten, why waste what is stored in case we have to fast? Normally, after each meal, the concentration of insulin increases, and it, in turn, along with the fact that it ensures normal glucose metabolism, suppresses lipolysis (the formation of FFA from triglycerides) in fat cells. And at night (if you don't eat at night), the level of FFA in plasma increases, because insulin in the blood drops, and this includes the synthesis of FFA from triglycerides. Almost all tissues, in particular skeletal muscles, "adjust" to these normal daily fluctuations in the levels of FFA in the blood, which "switch" from glucose utilization during the day to FFA consumption at night. The ability of skeletal muscles and other tissues to adjust their metabolism to the currently dominant substrate is called good "metabolic health", or "metabolic flexibility", which is associated with the normal sensitivity of cells (in particular, adipose tissue cells) to insulin. But there is one fabric that "works" on LPG fuel both day and night. This is the heart. Free fatty acids are the main metabolic resource for the myocardium.In the heart, FFA is rapidly metabolized due to beta-oxidation in the mitochondria, which provides from 65 to 70% of the ATP needed by the heart.

The heart receives the remaining 20-25% of ATP due to glycolysis. The "burning" of FFA is a very costly process: the oxidation of 1 mole of FFA requires more oxygen than the oxidation of 1 mole of glucose. And normally these oxygen needs are met.

It has been repeatedly and reliably shown that most people suffering from obesity and metabolic syndrome have elevated levels of FFA in blood plasma.

Violation of the metabolism of free fatty acids is a key event leading to insulin resistance. With obesity, excess FFA enters the bloodstream. Further depends on which tissues, not intended for storing excess FFA, they will accumulate. If in skeletal muscles – this will lead to IR. If in the liver – to dyslipidemia, i.e. to a violation of cholesterol metabolism, then to atherosclerosis, then to coronary artery disease. First, as a rule, insulin resistance develops, and then, with its aggravation, CHD.

FFA levels are a "matter of life and death" for pancreatic beta cells.It is these cells that synthesize insulin. It is they who are killed by excessive levels of free fatty acids. This is called the "lipotoxic effect". As a result, blood glucose levels rise, however, when elevated levels of FFA enter the liver, they stimulate the synthesis of endogenous glucose there. We need glucose (on which the brain mainly works) all the time. Normally, slightly elevated nighttime levels of FFA stimulate its synthesis in the liver. But pathologically elevated levels of FFA stimulate increased endogenous glucose synthesis around the clock. Thus, excess FFA leads to hyperglycemia in two different ways. Beta cells poisoned by an excess of FFA reduce insulin synthesis, and the liver, overloaded with FFA, begins to synthesize glucose. But there is a third road leading to hyperglycemia. It goes through the insensitivity (resistance) of cells to insulin.

What does the pathological metabolism of excess FFA lead to? To insulin resistance. And in two different ways. Firstly, due to a violation of the insulin signal transmission pathway caused by the pathological metabolism of FFA in skeletal muscles that cannot cope with the oxidation of excess FFA. Local accumulation of FFA metabolites such as ceramide, glycerol or Acyl CoA inside skeletal muscles disrupts the transmission of the insulin signal and, thereby, the transport of glucose into cells. Ceramides consist of a sphingoid base (sphingosine,) and a fatty acid residue connected by an amide bond.

Ceramide, an intermediate in the biosynthesis of sphingomyelin, is formed by the interaction of sphingosine with acyl-CoA. Ceramide is a secondary messenger in the so–called sphingomyelin signaling pathway, it participates in the regulation of cellular processes such as cell differentiation, cell proliferation, apoptosis (programmed cell death). As it turned out, in obese people suffering from IR, ceramide levels in skeletal muscles are increased by 2 times. This increase is associated with high levels of FFA in the blood and with a decrease in the intensity of phosphorylation of Akt protein kinase involved in the transmission of the insulin signal. Experiments with animals and pharmacological agents have shown that lowering ceramide levels (by inhibiting its synthesis) actually improves glucose homeostasis in insulin-resistant transgenic mice with obesity and diabetes.

The second mechanism of the occurrence of IR caused by an excess of FFA: a large mass of adipocytes (adipose tissue cells) synthesizes increased amounts of so–called proinflammatory cytokines (adipocytokines) - proteins that stimulate the inflammatory process. This leads to a chronic inflammatory process, which, in turn: a) disrupts the pathway of insulin signal transmission and b) damages the functions of mitochondria, which, as a result, disrupts glucose homeostasis. Thus, as soon as the level of FFA rises in the blood, expect trouble. In a few years.

An increase in the level of free fatty acids predicts the development of insulin resistance. In particular, a violation of glucose tolerance. What is the essence of the glucose tolerance test? After the first determination of the fasting blood glucose level, the patient takes 75 g of glucose diluted in 200 ml of water. The solution is slowly drunk for 10 minutes. The next measurement of blood glucose level is made 2 hours after the start of the syrup intake. If the sugar content in capillary whole blood taken on an empty stomach exceeds 120 mg%, and 2 hours after the sugar load – above 200 mg% (11.0 mmol / l), then this confirms the presence of diabetes mellitus. A violation of glucose tolerance is indicated if the sugar content in the blood taken on an empty stomach is below 120 mg% (7.0 mmol / l), and the sugar in the blood taken after 2 hours is between 140 and 200 mg% (7.8 and 11.0 mmol / l). A glucose tolerance test is considered negative (i.e. not confirming the diagnosis of diabetes) if the blood sugar taken on an empty stomach is below 120 mg% (7.0 mmol/L), and the blood sugar taken after 2 hours is below 140 mg% (7.8 mmol/L). In one of the studies, 3,671 people with initially normal glucose tolerance were observed for 5 years. During this time, 418 individuals developed impaired glucose tolerance. It was these individuals who had high levels of fasting FFA even when there was no violation of glucose tolerance yet. In another study, 580 people with DM2 and 556 healthy individuals (control group) were observed for 9 years. We found that the levels of FFA are directly proportional to: 1) with a degree of obesity, 2) with a waist size, 3) with a pulse rate, 4) plasma triglyceride (fat) levels, 5) with indicators of inflammation and 6) with the presence of DM2.

Thus, timely measured levels of FFA in the blood can warn in advance of the upcoming IR. And warned means armed. And it is necessary to arm yourself against an excess of SZHK. Because "the more of them, the more of them."

Insulin resistance further increases the level of free fatty acids. Have you forgotten that normally insulin suppresses the formation of FFA from triglycerides stored in adipose tissues? And if fat cells are not sensitive to insulin? Yes. You got it right. It has been repeatedly shown that insulin-resistant adipocytes secrete elevated levels of FFA. FFA in IR simply "flow" from fat into the blood. And the level of FFA in the blood is increasing more and more. The consequence stimulates its cause – there is a positive feedback between IR and the concentration of FFA in the blood. This leads us to believe that elevated levels of FFA in the blood are a diagnostic marker of IR. It is essential that IR fat cells intensively break down the triglycerides contained in them and release the FFA formed from them into the bloodstream both with and without obesity. All this has the most serious consequences.

Elevated levels of free fatty acids lead to atherosclerosis. FFA enters the liver, and there, as is known, the main reactions of cholesterol metabolism occur: synthesis and utilization of LDL and HDL. In the liver, excess FFA turns into excess triglycerides, and this leads to a "falling domino" effect in the chain of reactions of cholesterol metabolism. As a result, elevated levels of FFA lead to a decrease in the level of good "anti-atherogenic" HDL-C, to the formation of extremely atherogenic small dense particles of LDL-C and to an increase in plasma levels of triglycerides. Moreover, the increased level of FFA in insulin resistance causes supersynthesis of reactive oxygen species in mitochondria, which leads to the oxidation of LDL-C and modification of HDL-C, which, in turn, induces an inflammatory process in the walls of blood vessels, leads to the formation and accumulation of cholesterol plaques and to ischemia (oxygen starvation of the heart). By the way, have you forgotten that it takes a lot of _O2 to oxidize FFA? Have you figured it out yet? That ischemia further worsens an already difficult situation? After all, with it, FFA is poorly oxidized and their level increases.

Ischemia caused by high levels of FFA further increases the level of FFA. With ischemia, serious problems arise with the metabolism of FFA in the myocardium:

1. In ischemic conditions, glucose utilization prevails over the use of FFA.
2. The metabolism of FFA becomes pathological, lactate and hydrogen ions are formed inside ischemic cells.
3. This leads:

• a) to the degradation of myocardial contractility,
• b) diastolic dysfunction and
• c) reduction of arrhythmogenic threshold of cardiomyocytes.

In general, elevated plasma levels of FFA, regardless of other parameters, are associated with diastolic dysfunction of the left ventricle and lead to so-called diabetic cardiomyopathy. Thus, elevated levels of FFA are also the earliest diagnostic marker of ischemia. Example: out of 2103 men who initially did not have coronary heart disease, 144 developed coronary heart disease during 5 years of follow-up. It turned out that increased fasting levels of FFA were associated with a 2-fold increased risk of coronary heart disease. Moreover, it has been shown that elevated levels of FFA are proportional to the severity of ischemia and indicate the approach of acute myocardial infarction (AMI). One of the most important diagnostic markers of AMI is the appearance of special cardiac proteins (troponins) in the blood. They enter the bloodstream with myocardial necrosis. And an increase in FFA levels occurs in the absence of myocardial necrosis. In general, elevated levels of FFA are an indicator of the severity of ischemia in so–called troponin-negative patients in whom AMI has not yet occurred.

So, an increase in the level of FFA drags the patient into a dead loop of pathological events, from which there are two ways out: to return to horizontal flight, primarily due to changes in eating behavior, or sooner or later to break into a peak or a corkscrew.  

In foreign medical literature, FGC is sometimes called the "red light on the dashboard of the myocardium." Indeed, an increase in their plasma levels signals an increasing danger. First about the metabolic syndrome, then about insulin resistance. And then – about diabetic cardiomyopathy.

When this "light bulb" lights up quite brightly – about coronary heart disease. And then this light bulb can burn out and the "light bulbs" of markers of myocardial necrosis will flash. And quite often, necrosis markers indicate that the "point of no return" has already been passed, that the consequences of ischemia are almost irreversible.

But elevated levels of FFA begin to "glow red" long before this point. When there is still time to change course.

"But I didn't hear the fat penguin
None of these screams..."

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18.03.2009