The cause of nonalcoholic fatty liver disease is complex and not completely understood. The most important factors appear to be the presence of obesity and diabetes. It used to be thought that obesity was nothing more than the simple accumulation of fat in the body. Fat tissues were thought to be inert, that is, they served as simply storage sites for fat and had little activity or interactions with other tissues. We now know that fat tissue is very active metabolically and has interactions and effects on tissues throughout the body.

When large amounts of fat are present as they are in obesity, the fat becomes metabolically active (actually inflamed) and gives rise to the production of many hormones and proteins that are released into the blood and have effects on cells throughout the body. One of the many effects of these hormones and proteins is to promote insulin resistance in cells.

Insulin resistance is a state in which the cells of the body do not respond adequately to insulin, a hormone produced by the pancreas. Insulin is important because it is a major promoter of glucose (sugar) uptake from the blood by cells. At first, the pancreas compensates for the insensitivity to insulin by making and releasing more insulin, but eventually it can no longer produce sufficient quantities of insulin and, in fact, may begin to produce decreasing amounts. At this point, not enough sugar enters cells, and it begins to accumulate in the blood, a state known as diabetes. Although sugar in the blood is present in large amounts, the insensitivity to insulin prevents the cells from receiving enough sugar. Since sugar is an important source of energy for cells and allows them to carry out their specialized functions, the lack of sugar begins to alter the way in which the cells function.

In addition to releasing hormones and proteins, the fat cells also begin to release some of the fat that is being stored in them in the form of fatty acids. As a result, there is an increase in the blood levels of fatty acids. This is important because large amounts of certain types of fatty acids are toxic to cells.

The release of hormones, proteins, and fatty acids from fat cells affects cells throughout the body in different ways. Liver cells, like many other cells in the body, become insulin resistant, and their metabolic processes, including their handling of fat, become altered. The liver cells increase their uptake of fatty acids from the blood where fatty acids are in abundance. Within the liver cells, the fatty acids are changed into storage fat, and the fat accumulates. At the same time, the ability of the liver to dispose of or export the accumulated fat is reduced. In addition, the liver itself continues to produce fat and to receive fat from the diet. The result is that fat accumulates to an even greater extent.