The aberrant accumulation of lipids in the liver (fatty liver) is tightly associated with several components of the metabolic syndrome, including type 2 diabetes, coronary heart disease, and atherosclerosis. Here we show that the impaired hepatic expression of transcriptional cofactor transducin beta-like (TBL) 1 represents a common feature of mono- and multigenic fatty liver mouse models. Indeed, the liver-specific ablation of TBL1 gene expression in healthy mice promoted hypertriglyceridemia and hepatic steatosis under both normal and high-fat dietary conditions. TBL1 deficiency resulted in inhibition of fatty acid oxidation due to impaired functional cooperation with its heterodimerization partner TBL-related (TBLR) 1 and the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α. As TBL1 expression levels were found to also inversely correlate with liver fat content in human patients, the lack of hepatic TBL1/TBLR1 cofactor activity may represent a molecular rationale for hepatic steatosis in subjects with obesity and the metabolic syndrome.
From press release:
Excess fat around the hips and belly may not really be compatible with current beauty ideals, but, to a certain degree, it is a normal, even vital energy store of our body. However, it is a different matter if the organism stores fat in organs such as the liver, pancreas or muscles. This is a clear sign of a metabolic disorder.
Up to 80 percent of obese people develop fatty liver disease, which is regarded a typical characteristic of the dangerous metabolic syndrome. Deposition of fat in the liver may lead to chronic liver inflammation and even to liver cancer. In addition, fatty liver is considered to be an independent risk factor for coronary heart disease and atherosclerosis.
The great medical relevance of fatty liver as a severe condition accompanying insulin resistance and type II diabetes caused the research group headed by Dr. Stephan Herzig of the Division of Molecular Metabolic Control to investigate how this syndrome arises. Which molecular switches are turned on or off in a cell when food delivers too much energy-rich fat molecules, or triglycerides?
To this end, the investigators determined the level of particular proteins involved in specific gene activation in the liver tissue of mice. These proteins, which are known as transcriptional co-activators, regulate which proteins are read and transcribed into messenger RNA molecules in a cell. In overweight mice, the researchers observed that a high triglyceride level in the liver was always associated with reduced production of a co-activator called TBL1. This was found both in animals that developed fatty liver for hereditary reasons and in those animals that received calorie-rich food.
TBL1 was originally discovered in connection with a rare hereditary hearing disorder. In the liver, but not in other tissues, an oversupply of fat reduces the production of TBL1. As a result, fat burning in the liver is reduced so that more fat molecules are deposited in liver cells. "This, in turn, may lead to a further reduction of TBL1," says Stephan Herzig.
Not only in mice is TBL1 linked to the liver fat (lipid) metabolism. The group found the same pattern in human liver tissue samples: the higher their triglyceride levels, the lower their TBL1 levels.
Stephan Herzig expects a practical use of these results. "We might be able in the future to use TBL1 levels for identifying those obese persons who have a special risk of developing fatty liver. We could then give specific dietary recommendations to counteract this."
Latest Articles
