Bile Acids Induce Inflammatory Genes in Hepatocytes

Abstract

Inflammation contributes to liver injury during cholestasis. The mechanism by which cholestasis initiates an inflammatory response in the liver, however, is not known. Two hypotheses were investigated in the present studies. First, activation of Toll-like receptor 4 (TLR4), either by bacterial lipopolysaccharide or by damage-associated molecular pattern molecules released from dead hepatocytes, triggers an inflammatory response. Second, bile acids act as inflammagens, and directly activate signaling pathways in hepatocytes that stimulate production of proinflammatory mediators. Liver inflammation was not affected in lipopolysaccharide-resistant C3H/HeJ mice after bile duct ligation, indicating that Toll-like receptor 4 is not required for initiation of inflammation. Treatment of hepatocytes with bile acids did not directly cause cell toxicity but increased the expression of numerous proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and other proteins that influence immune cell levels and function. Upregulation of several of these genes in hepatocytes and in the liver after bile duct ligation required early growth response factor-1, but not farnesoid X receptor. In addition, early growth response factor-1 was up-regulated in the livers of patients with cholestasis and correlated with levels of inflammatory mediators. These data demonstrate that Toll-like receptor 4 is not required for the initiation of acute inflammation during cholestasis. In contrast, bile acids directly activate a signaling network in hepatocytes that promotes hepatic inflammation during cholestasis.

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

“…This massive accumulation of bile acids in hepatocytes might initiate a negative-feedback mechanism that results in the observed gene expression reduction. Simultaneously, accumulation of toxic intracellular bile acid levels resulted in cell death, necrosis, and induction of inflammatory mediators (46,47). We supposed that necrosis and leakage of hepatocellular contents explained the increased serum TBA levels despite the CYP7A1 and CYP8B1 gene repression in INH-LPS-cotreated animals.…”

The Role of Inflammation in the Mechanisms of Bile Acid-Induced Liver Damage

“…In the last decade, a number of studies have suggested that bile acids may injure liver cells in cholestatic liver disease, not by a direct toxic effects as a detergent, but by initiating a cytokine-mediated inflammatory response [1,2]. While there is little doubt that bile acids can injure mitochondria, produce oxidative stress and initiate Fas-dependent apoptosis, these observations have been derived primarily from in-vitro studies in isolated cell systems where the concentrations have exceeded those normally found in the serum or liver of cholestatic animal models or patients with cholestatic liver diseases [3,4,5].…”

“…Allen et al [1] have shown that the exposure of hepatocytes in culture to levels of bile acids (both toxic and non-toxic) that are seen in-vivo, results in significant increases in mRNA expression of pro-inflammatory cytokines, particularly CXCL2 (MIP-2) and CXCL1 (KC). Importantly, toll-like receptor 4 was not involved in the initiation of this acute inflammatory response [1]. …”

Transformation of chenodeoxycholic acid by thermophilic Geobacillus stearothermophilus

“…Besides their established role in metabolism, they also act as signaling molecules with systemic endocrine functions [2]. Thus, BAs are involved in cell-signaling receptors such as farnesoid X receptors and G-protein-coupled receptors, making them important for the biotechnological production of new steroid drugs [3].…”