Lipotoxicity is a

metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndrom ...

that results from the accumulation of

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids incl ...

intermediates in non-

adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

, leading to cellular dysfunction and

death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

. The tissues normally affected include the

kidneys The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

heart The heart is a muscular organ found in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon diox ...

and

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...

. Lipotoxicity is believed to have a role in

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

, and

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

, and is estimated to affect approximately 25% of the adult American population.

Cause

In normal cellular operations, there is a balance between the production of lipids, and their oxidation or transport. In lipotoxic cells, there is an imbalance between the amount of lipids produced and the amount used. Upon entrance of the cell, fatty acids can be converted to different types of lipids for storage.

Triacylglycerol A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from '' tri-'' and '' glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, a ...

consists of three fatty acids bound to a

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids know ...

molecule and is considered the most neutral and harmless type of intracellular lipid storage. Alternatively, fatty acids can be converted to lipid intermediates like

diacylglycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as sur ...

, ceramides and fatty acyl-CoAs. These lipid intermediates can impair cellular function, which is referred to as lipotoxicity.Bosma M, Kersten S, Hesselink MKC, and Schrauwen P. Re-evaluating lipotoxic triggers in skeletal muscle: Relating intramyocellular lipid metabolism to insulin sensitivity. Prog Lipid Res 2012; 51: 36-49, doi=10.1016/j.plipres.2011.11.003 Adipocytes, the cells that normally function as lipid store of the body, are well equipped to handle the excess lipids. Yet, too great of an excess will overburden these cells and cause a spillover into non-adipose cells, which do not have the necessary storage space. When the storage capacity of non-adipose cells is exceeded, cellular dysfunction and/or death result. The mechanism by which lipotoxicity causes death and dysfunction is not well understood. The cause of apoptosis and extent of cellular dysfunction is related to the type of cell affected, as well as the type and quantity of excess lipids. A theory has been put forward by Cambridge researchers relating the development of lipotoxicity to the perturbation of membrane glycerophospholipid/sphingolipid homeostasis and their associated signalling events. Currently, there is no universally accepted theory for why certain individuals are afflicted with lipotoxicity. Research is ongoing into a genetic cause, but no individual

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

has been named as the causative agent. The causative role of obesity in lipotoxicity is controversial. Some researchers claim that obesity has protective effects against lipotoxicity as it results in extra adipose tissue in which excess lipids can be stored. Others claim obesity is a risk factor for lipotoxicity. Both sides accept that high fat diets put patients at increased risk for lipotoxic cells. Individuals with high numbers of lipotoxic cells usually experience both leptin and

insulin resistance Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood suga ...

. However, no causative mechanism has been found for this correlation.

Effects in different organs

Kidneys

Renal lipotoxicity occurs when excess long-chain nonesterified fatty acids are stored in the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

and proximal tubule cells. It is believed that these fatty acids are delivered to the kidneys via serum albumin. This condition leads to tubulointerstitial inflammation and

fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of permane ...

in mild cases, and to

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

and death in severe cases. The current accepted treatments for lipotoxicity in renal cells are fibrate therapy and intensive

insulin therapy As a medication, insulin is any pharmaceutical preparation of the protein hormone insulin that is used to treat high blood glucose. Such conditions include type 1 diabetes, type 2 diabetes, gestational diabetes, and complications of diabet ...

Liver

An excess of free fatty acids in liver cells plays a role in Nonalcoholic Fatty Liver Disease (NAFLD). In the liver, it is the type of fatty acid, not the quantity, that determines the extent of the lipotoxic effects. In hepatocytes, the ratio of monounsaturated fatty acids and saturated fatty acids leads to apoptosis and liver damage. There are several potential mechanisms by which the excess fatty acids can cause cell death and damage. They may activate death receptors, stimulate apoptotic pathways, or initiate

cellular stress response Cellular stress response is the wide range of molecular changes that cells undergo in response to environmental stressors, including extremes of temperature, exposure to toxins, and mechanical damage. Cellular stress responses can also be caused ...

in the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

. These lipotoxic effects have been shown to be prevented by the presence of excess triglycerides within the hepatocytes.

Heart

Lipotoxicity in cardiac tissue is attributed to excess saturated fatty acids. The apoptosis that follows is believed to be caused by unfolded protein response in the endoplasmic reticulum. Researchers are working on treatments that will increase the oxidation of these fatty acids within the heart in order to prevent the lipotoxic effects.

Pancreas

Lipotoxicity affects the pancreas when excess free fatty acids are found in beta cells, causing their dysfunction and death. The effects of the lipotoxicity is treated with leptin therapy and insulin sensitizers.

Skeletal muscle

The skeletal muscle accounts for more than 80 percent of the postprandial whole body glucose uptake and therefore plays an important role in glucose homeostasis. Skeletal muscle lipid levels – intramyocellular lipids (IMCL) – correlate negatively with insulin sensitivity in a sedentary population and hence were considered predictive for insulin resistance and causative in obesity-associated insulin resistance. However, endurance athletes also have high IMCL levels despite being highly insulin sensitive, which indicates that not the level of IMCL accumulation per se, but rather the characteristics of this intramyocellular fat determine whether it negatively affects insulin signaling. Intramyocellular lipids are mainly stored in

lipid droplets Lipid droplets, also referred to as lipid bodies, oil bodies or adiposomes, are lipid-rich cellular organelles that regulate the storage and hydrolysis of neutral lipids and are found largely in the adipose tissue. They also serve as a reservoir ...

, the organelles for fat storage. Recent research indicates that creating intramyocellular neutral lipid storage capacity for example by increasing the abundance of lipid droplet coat proteins protects against obesity-associated insulin resistance in skeletal muscle.

Prevention and treatment

The methods to prevent and treat lipotoxicity are divided into three main groups. The first strategy focuses on decreasing the lipid content of non-adipose tissues. This can be accomplished by either increasing the oxidation of the lipids, or increasing their secretion and transport. Current treatments involve extreme weight loss and leptin treatment. Another strategy is focusing on diverting excess lipids away from non-adipose tissues, and towards adipose tissues. This is accomplished with thiazolidinediones, a group of medications that activate

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of s ...

proteins responsible for lipid metabolism. The final strategy focuses on inhibiting the apoptotic pathways and signaling cascades. This is accomplished by using drugs that inhibit production of specific chemicals required for the pathways to be functional. While this may prove to the most effective protection against cell death, it will also require the most research and development due to the specificity required of the medications.

References

{{reflist Diabetes Metabolism Lipids