Changes in lipid intake or metabolism can affect development of liver injury and fibrosis, according to two studies in mice published in the January issue of Gastroenterology.
The liver is an important site of energy production and lipid metabolism. However, accumulation of excess fat in the liver promotes development of fibrosis, cirrhosis and hepatocellular cancer. Not much is known about how lipids and lipid metabolism influence liver diseases. Two studies used mice to learn more.
Teratani et al. investigated the effects of a high cholesterol diet on hepatic fibrosis induced by bile duct ligation or carbon tetrachloride, which cause biliary and toxic liver injury.The diet did not affect hepatocytes, but increased levels of cholesterol in hepatic stellate cells (HSCs; liver cells that store lipid and promote fibrogenesis) and increased up-regulation of profibrogenic genes in response to transforming growth factor (TGF)-β.
Although the high-cholesterol diet did not affect expression of the receptor for TGF-β, the authors observed increased levels of the lipopolysaccharide Toll-like receptor (TLR)4, and other alterations in this hepatocyte signaling pathway. Cholesterol did not increase levels of TLR4 mRNA, so the authors to propose that cholesterol prevents degradation of TLR4 protein. This is one of the first studies to show that cholesterol affects HSCs and their fibrogenic abilities.
Moustafa et al. uncovered a unique role for hepatic lipids using a mouse model of cholestatic liver disease, caused by genetic disruption of the ATP-binding cassette sub-family B member 4 (Abcb4−/−). Abcb4 encodes a phospholipid flippase that promotes biliary secretion of phospholipid and protects the biliary epithelium from the damaging effects of bile acids. Mice deficient in Abcb4 develop hepatocellular injury, cholestasis, and liver fibrosis. ABCB4 mutations in humans cause progressive familial intrahepatic cholestasis type 3 (PFIC3).
In the in Abcb4−/− mice, 24-NorUrsodeoxycholic acid (NorUDCA, a side-chain variant of ursodeoxycholic acid that ameliorates cholestatic liver injury), loss of PPAR-α (PPAR-/-), and the high-fat diet (HFD, in figure below) reduced cholestasis, hepatic inflammation and fibrosis. The improvements coincided with reductions in activities of hepatic phospholipase and triglyceride lipase.
These results were surprising because they show that hepatic lipid homeostasis in an important determinant of outcome in a liver disease not characterized by hepatic steatosis. They are also unique in that they demonstrate cholestatic liver disease, at least in Abcb4−/−mice, is improved by increasing, rather than decreasing, hepatic triglyceride levels.
In an editorial that accompanies the articles, Robert Schwab and Jacquelyn Maher ask whether this means that there is some optimal level of hepatic triglyceride—that disease develops if there is too much or too little? They say that the answer is no—instead, the development of liver disease depends on the metabolic activity of hepatic lipid. Excess fatty acids in the liver are dangerous only when they are prevented from being incorporated into triglycerides, and the findings of Moustafa et al. show that liver injury can also occur if lipid droplets are unable to hold on to their triglyceride. Schwab and Maher conclude that these findings incriminate fatty acids as hepatotoxic compounds and support the concept that triglyceride synthesis in hepatocytes is a cytoprotective mechanism.
Although Abcb4−/− mice are a model of human cholestatic liver disease, it is not clear if the lipid-related abnormalities in these mice can be compared to those of patients—even patients with PFIC3. It will be important to determine whether patients with PFIC3 have the same reduction of hepatic triglycerides and increased triglyceride hydrolysis as Abcb4−/− mice. If so, these findings could lead to a new therapeutic approach for this disease.
Read the articles online:
Teratani T, Tomita K, Suzuki T, et al. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 2012;152–164.e10.
Moustafa T, Fickert P, Magnes C, et al. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 2012; 140–151.e12
Read the accompanying editorial.
Schwabe RF, Maher JJ. Lipids in liver disease: looking beyond steatosis. Gastroenterology 2012;8–11.