Integrative Metabolism & Physiology: The case for Lipotoxicity

When trying to understand human metabolism and physiology, one must consider an organism as a whole. Because of our human nature, we tend to synthesize most of the available information to the point of applying the Occam's razor principle incorrectly. Living organisms are open systems in which every metabolic pathway is interrelated, maintaining a dynamic steady state. This is one of the main issues of studying cells in vitro versus in vivo.

As I pointed out in my introductory post, every human biological process has its purpose. There are not "bad" molecules or "good" ones. Glycolysis is not bad, excessive glycolisis is bad. Lipolysis is not bad, excessive lipolysis is bad. And so on. Considering this principle is essential for understanding modern diseases, treating and preventing them. Modern medicine has made the huge mistake of applying the bad/good concept for trying to understand diseases. We should not try to understand diseases only by proximate causes, but by evolutionary causes as well (for an in depth review, see Harris and Malyango, 2005). 

Lately, IR is one hot topic in the scientific community as well as in the blogosphere. Because of its implication in almost every modern disease, many apply the "morality principle", by which IR is bad and IS is good. If you ask the regular health reader the question "Is IR bad?" you will probably hear an unanimous YES!. On the contrary, my answer would be "it depends". 

To undestand why something completely normal like IR goes pathological we have to look at the Randle Cycle. In a nutshell, every substrate promotes its own oxidation. If you eat more glucose, you burn more glucose; if you eat more fat, you burn more fat*. The human body has adapted to use both sources of fuel as energy. Early humans evolved in highly different ecological niches, some with an increased amount of sugar/starch and others with less or none. Mechanisms should have been developed for coupling both energy substrates. When the main source of fuel is glucose, the expression of key enzymes involved in glycolisis increases. Glut-4 translocation increases for clearing glucose more efficiently from the bloodstream. Insulin reduces the rate of lipolysis by downregulating HSL, so less FFA are used for energy. Glucose itself promotes its storage, both as glycogen or fat, directly or indirectly (activation of hepatic/adipose DNL, ChREBP and several lipogenic genes, etc.). On the contrary, when you eat more fat, you will use more fat. Fat ingestion produces an increase in lipolysis and beta-oxidation. CPTI, UCP, CD36/FAT are all increased. Because the insulin response to fat is null, HSL is not supressed and lipolysis serves to deliver the necessary energy for the tissues. If more FFA than needed are released, re-esterification occurs. Excess flux of FFA to the liver produces KB to reduce the need for glucose and to control the rate of lipolysis. 

There are some cells that can only use glucose. GnG is the mechanism by which we evolved to supply this demand in a coordinate way: there is never going to be "too much" glucose produced by GnG. When carbohydrate intake is reduced drastically, we supply the exact amount to these cells by this mechanism. We rely less on glycogenolisis and more on GnG for controlling glycemia. Peripheral IR develops to redistribute the produced glucose to the glucose-strict using cells. The muscle functions as well or better with FFA and KB, and has its own glucose reserovir. There is no evolutionary logic on relying on glucose when you have more efficient fuels readily avilable. Palmitate is the key metabolic mediator in this process. It serves as an intercellular signal that integrates energy metabolism, reducing the utilization of glucose and increasing fat oxidation. Peter from Hyperlipid has written about this before in his Physiological Insulin Resistance series.

In a normal physiological scenario the body is adapted to handle increased amounts of glucose or FFA in plasma. Is abnormal to have both substrates high at the same time. If this happens it means that you have a dysregulated metabolism. And here is where the main problems of interpretation arise when evaluating pathological IR. Some say the culprit is high glucose. Others say its lipotoxicity. This last mechanism has gotten much attention lately because of the rise of carb conscious bloggers who dismiss the insulin/carbohydrate hypothesis. Lipotoxicity is the mechanism by which high plasma FFA concentrations produce deleterious metabolic effects. Lets think for a second. We store energy as fat. We use energy as fat. We store fat mainly as palmitate (the principal muscle IR agent and responsible for modern diseases). When we need energy, we hydrolize TG and free palmitate into plasma. High palmitate and high FFA produces lipotoxicity and IR, so then, are we designed to kill ourselves? The answer is obviously no. Lipotoxicity only occurs if there is a mismatch between lipolysis and beta-oxidation. For instance, there is evidence that saturated FA trigger a specific inflammatory response in coronary artery endothelial cells (1), lipoapoptosis (2) and endothelial dysfunction (3). When skeletal muscle cells are exposed to increased levels of palmitate, we see that the deleterious effects build-up dose dependently (4). This means that while myocites can handle a physiological increase in palmitate, they start to develop defense mechanisms when levels rise to pathological. This only occurs in abnormal or broken** metabolisms, like in T2DM. Having endothelial cells chronically exposed to very high FFA is bad, so muscle cells try to reduce this exposure by storing lipids as IMTG. Accordingly, IR has been proposed as a defense mechanism for controlling body fat distribution (5). NEFAs have also shown to impair insulin secretion, possibly as a preventive mechanism (6).

So for lipotoxicity to occur, there must be a metabolic dysregulation by which the rate of lipolysis is not controlled. As we all know, insulin is the key enzyme controlling HSL. It has been proposed that adipose tissue IR (ATIR) is the starting point in the pathogenesis of pathological IR (7). Without insulin, lipolysis is unregulated. Because this is not due to a physiological need***, oxidation is not correlated with lipolysis and FFA start to rise in plasma and accumulate in extra-adipose tissues. But pathological IR is not characterized only by  ATIR. Loss of control of GnG also occurs because of hepatic IR, producing hyperglycemia. Now the body has two potential fuels in excess and each one promotes its own oxidation. To compensate, hyperinsulinemia occurs and aggravates the situation. Chronic hyperinsulinemia and hyperglicemia, without an excess of FFA, have shown to impair insulin sensitivity and insulin secretion (8) by a different mechanism (impaired non-oxidative glucose disposal). This, combined with high plasma FFA is a recipe for disaster. 

When talking about lipotoxicity one must be careful with the evidence. As I stated, we cannot make conclusions based only on in vitro studies. When you eat no carbohydrates (or at least not intentionally) FFA will and should rise in plasma. Its completely normal, you use fat as fuel, you need it available. Just like ketosis. But if you eat carbohydrates, you shouldn't have elevated FFA nor ketones. This is when lipotoxicity occurs. 

Bottomline: Each metabolic fuel controls its own oxidation. We cannot use isolated mechanisms or variables to try to understand physiology and metabolism as the body is a highly regulated and integrated system. Arguing that FFA in plasma cause lipotoxicity is as misleading and wrong as saying that insulin by itself causes insulin resistance. 

* Not necessarily your own body fat. 
** As per the definition of Dr. Harris.
*** You need energy = you burn more fat (increased rate of lipolysis). FFA are supplied according to the energy demand and oxidized.