Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver conditions in the United States, affecting 30 percent of the population, and increasing — and likely to catch up in prevalence with obesity and diabetes. In NAFLD, fat content of the liver is elevated to 6 percent or more in people who drink in moderation or not at all. Patients will first present with elevated liver enzyme values in blood tests, but then an imaging test or tissue biopsy may be ordered to evaluate the extent of the damage. NAFLD is mostly asymptomatic and is variable in severity; a majority of those afflicted do not need drug treatments. However, NAFLD is thought to be a preliminary condition that can eventually progress to severe manifestations, such as cirrhosis, hepatocellular carcinoma, and end stage liver failure.
At Emory, Frank Anania, director of the Department of Medicineâ€™s Division of Digestive Diseases, and his colleagues are developing a tool to treat liver disease. A recent publication in the FASEB Journal describes their investigation into the potential for the hormone adiponectin to modulate liver fibrosis.
Adiponectin is produced by adipose tissue, but is known to decrease in overweight people with metabolic disease. Research by others indicates that it may prevent heart and kidney fibrosis. The Emory teamâ€™s studies were conducted to determine if adiponectin could also reduce liver fibrosis.
In the fatty liver, disease begins with inflammation and scarring, potentially brought on by viral infection or toxins. Hepatic stellate cells, which play a key role in the development of fibrosis, become activated and secrete extracellular matrix proteins such as collagen that harden the tissue to facilitate the healing process. This process, can be reversed by the activity of metalloproteinases that break down collagen fibers. But it can also progressively worsen to the point of portal vein hypertension, in which the liverâ€™s blood supply becomes slowed or blocked and the organ becomes dysfunctional.
In the FASEB Journal paper, the authors evaluated how liver disease progresses in adiponectin knock out, carbon tetrachloride fed mice. Reduced disease severity was seen in mice that were rescued with adiponectin. They also examined the chemical signaling pathways in hepatic stellate cells,. These cells are known to interact with adiponectin by either of two receptor proteins, adipoR1 and adipoR2. Their experiments suggest that adiponectin can bind AdipoR1, and via a special cytoplasmic adaptor protein (APPL1), block the activation of stellate cells and deposition of collagen.
In one of their experiments, they examined the functioning of a recently developed drug candidate, adiponectin-like peptide, ADP355. Their work showed it could prevent activation of focal adhesion kinase 1 (FAK1), a key step preceding the activation of hepatic stellate cells, indicating ADP355 has the potential to halt collagen secretion and slow the progression of liver disease.
Adiponectin, is a high molecular weight hormone that is difficult to manufacture, and thus thought not to be an ideal drug candidate. The ADP355 peptide conveys adiponectin-like properties and is easy to synthesize. Research on this front is in the beginning stages of testing and has not entered the clinic for human research trials. Several number of drugs are now being evaluated for treatment of fibrosis. If successful, ADP355 may rival one of these candidates currently in clinical trials:
IDN-6556: caspase inhibitor
GR-MD-02: galectin 3 antagonist
ND-L02-sO201: siRNA of SERPINH
Losartan: angiotension receptor blocker
LDE225: hedgehog inhibitor
Aramchol: bile acid conjugate that affects fatty acid metabolism