Activating Transcription Factor 3 Protects against Restraint Stress-Induced Gastrointestinal Injury in Mice

Psychological stress increases the risk of gastrointestinal (GI) tract diseases, which involve bidirectional communication of the GI and nerves systems. Acute stress leads to GI ulcers; however, the mechanism of the native cellular protection pathway, which safeguards tissue integrality and maintains GI homeostasis, remains to be investigated. In a mouse model of this study, restraint stress induced GI leakage, abnormal tight junction protein expression, and cell death of gut epithelial cells. The expression of activating transcription factor 3 (ATF3), a stress-responsive transcription factor, is upregulated in the GI tissues of stressed animals. ATF3-deficient mice displayed an exacerbated phenotype of GI injuries. These results suggested that, in response to stress, ATF3 is part of the native cellular protective pathway in the GI system, which could be a molecular target for managing psychological stress-induced GI tract diseases.

Hepatocytic activating transcription factor 3 protects against steatohepatitis via hepatocyte nuclear factor 4

Activating transcription factor 3 (ATF3) has been shown to play an important role in HDL metabolism, yet the role of hepatocytic ATF3 in the development of steatohepatitis remains elusive. Here we show that adeno-associated virus-mediated over-expression of human ATF3 in hepatocytes prevents diet-induced steatohepatitis in C57BL/6 mice and reverses steatohepatitis in <i>db/db</i> mice. Conversely, global or hepatocyte-specific loss of ATF3 aggravates diet-induced steatohepatitis. Mechanistically, hepatocytic ATF3 induces hepatic lipolysis and fatty acid oxidation and inhibits inflammation and apoptosis. We further show that hepatocyte nuclear factor 4a (HNF4a) is required for ATF3 to improve steatohepatitis. Thus, the current study indicates that ATF3 protects against steatohepatitis through, at least in part, hepatic HNF4a. Targeting hepatic ATF3 may be useful for treatment of steatohepatitis.

Hepatocytic activating transcription factor 3 protects against steatohepatitis via hepatocyte nuclear factor 4

Activating transcription factor 3 (ATF3) has been shown to play an important role in HDL metabolism, yet the role of hepatocytic ATF3 in the development of steatohepatitis remains elusive. Here we show that adeno-associated virus-mediated over-expression of human ATF3 in hepatocytes prevents diet-induced steatohepatitis in C57BL/6 mice and reverses steatohepatitis in <i>db/db</i> mice. Conversely, global or hepatocyte-specific loss of ATF3 aggravates diet-induced steatohepatitis. Mechanistically, hepatocytic ATF3 induces hepatic lipolysis and fatty acid oxidation and inhibits inflammation and apoptosis. We further show that hepatocyte nuclear factor 4a (HNF4a) is required for ATF3 to improve steatohepatitis. Thus, the current study indicates that ATF3 protects against steatohepatitis through, at least in part, hepatic HNF4a. Targeting hepatic ATF3 may be useful for treatment of steatohepatitis.

Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy

We investigated the mediating roles of activating transcription factor 3 (ATF3), an injury marker, or C-type lectin member 5A (CLEC5A), an inflammatory response molecule, in the induction of endoplasmic reticulum (ER) stress and neuroinflammation in diabetic peripheral neuropathy in ATF3 and CLEC5A genetic knockout (aft3−/− and clec5a−/−, respectively) mice. ATF3 was expressed intranuclearly and was upregulated in mice with diabetic peripheral neuropathy (DN) and clec5a−/− mice. The DN and clec5a−/− groups also exhibited neuropathic behavior, but not in the aft3−/− group. The upregulation profiles of cytoplasmic polyadenylation element-binding protein, a protein translation–regulating molecule, and the ER stress-related molecules of inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α in the DN and clec5a−/− groups were correlated with neuropathic behavior. Ultrastructural evidence confirmed ER stress induction and neuroinflammation, including microglial enlargement and proinflammatory cytokine release, in the DN and clec5a−/− mice. By contrast, the induction of ER stress and neuroinflammation did not occur in the aft3−/− mice. Furthermore, the mRNA of reactive oxygen species–removing enzymes such as superoxide dismutase, heme oxygenase-1, and catalase were downregulated in the DN and clec5a−/− groups but were not changed in the aft3−/− group. Taken together, the results indicate that intraneuronal ATF3, but not CLEC5A, mediates the induction of ER stress and neuroinflammation associated with diabetic neuropathy.