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The liver is part of the gastrointestinal tract, it filters blood coming from the GI tract before the blood circulates to the rest of the body. Its myriad of functions include secreting bile, which helps us absorb fats and eliminate waste; producing cholesterol, triglycerides and blood clotting factors; and detoxifying chemicals. The liver is the heaviest solid organ in the body and sits on the right sight of the body behind the lower ribs.The most common causes of liver damage include infection with the hepatitis B or C virus, heavy alcohol use, obesity and diabetes.
Obesity and alcoholism trigger a receptor that increases the inflammation in response to invaders like bacteria in liver. The increased activity of TREM-1 in turn accelerates injury and scarring of the liver, a first step toward cirrhosis and liver cancer, says Dr. Anatolij Horuzsko, reproductive immunologist in the Georgia Cancer Center and Department of Medicine at the Medical College of Georgia at Augusta University.
TREM-1, or triggering receptor expressed on myeloid cells-1 turns up inflammation short-term to deal with external invaders. It has increased activity immediately after an injury as well, when increased inflammation, damage cleanup and collagen production aid healing. But when activated by chronic offending agents, like obesity and hepatitis, TREM-1 contributes to a destructive level of inflammation that results in liver damage and cancer.
The unhealthy transformation can occur in five to 50 years, depending on factors like the level of insult, and may be largely reversible up to the point of cirrhosis, if the offending agent is stopped, and the liver’s natural ability to regenerate takes over.
It’s known that inflammation is a key process in the thickening and scarring of the liver fibrosis, and that tamping down inflammation can prevent fibrosis progression. In the liver, TREM-1 is found primarily on Kupffer cells, the liver’s resident macrophages, as well as monocytes, a type of white blood cell that can also become garbage-eating macrophages. TREM-1’s expression is limited in a healthy human liver but its activation goes up short-term following an insult, like a laceration.
Researchers created a model of chronic liver diseaselike obesity or high alcohol consumption might using carbon tetrachloride, a poisonous solvent found in oils, varnishes and resin. They found TREM-1 activation went up and stayed up on a larger number of Kupffer cells in the liver as well as other immune cells circulating in the body.
When they deleted TREM-1 from the model, it reduced inflammation, injury and subsequent fibrosis. When they gave TREM-1 back to the mice, inflammation and related damage came back with a vengeance, leading them to dub TREM-1 the main target that drives fibrogenesis. They found TREM-1 even recruits other pro-inflammatory cells from the bone marrow to the liver, many of which could become macrophages as well, which further multiplies the inflammation, liver cell damage and death.
Collagen is a component of connective tissue that typically holds tissues and blood vessels together and aids wound healing. The liver already has some collagen, but in this case too much gets deposited and liver function suffers. Efficiency goes down and it causes additional damage to liver cells that already have been damaged by hepatitis or obesity.
Blood levels of the enzymes alanine aminotransferase, or ALT, and aspartate aminotransferase, or AST, are indicators of liver injury and both went up and remained high in their models. However, in mice where TREM-1 was knocked out, rates went up only short- term before returning to pre-injury levels, another indicator of TREM-1’s role in persistent inflammation and resulting damage, Horuzsko says.
They also found that while mice with and without TREM-1 both recruited additional immune cells, such as more macrophages and monocytes, from their bone marrow immediately after the injury, 72 hours later the levels were much higher both in the blood and livers of the mice that also still had TREM-1.