Autophagy confers resistance to lipopolysaccharide-induced mouse hepatocyte injury

Abstract

During sepsis, bacterial products, particularly LPS, trigger injury in organs such as the liver. This common condition remains largely untreatable, in part due to a lack of understanding of how high concentrations of LPS cause cellular injury. In the liver, the lysosomal degradative pathway of autophagy performs essential hepatoprotective functions and is induced by LPS. We, therefore, examined whether hepatocyte autophagy protects against liver injury from septic levels of LPS. Mice with an inducible hepatocyte-specific knockout of the critical autophagy gene Atg7 were examined for their sensitivity to high-dose LPS. Increased liver injury occurred in knockout mice, as determined by significantly increased serum alanine aminotransferase levels, histological evidence of liver injury, terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, and effector caspase-3 and -7 activation. Hepatic inflammation and proinflammatory cytokine induction were unaffected by the decrease in hepatocyte autophagy. Although knockout mice had normal NF-κB signaling, hepatic levels of Akt1 and Akt2 phosphorylation in response to LPS were decreased. Cultured hepatocytes from knockout mice displayed a generalized defect in Akt signaling in response to multiple stimuli, including LPS, TNF, and IL-1β. Akt activation mediates hepatocyte resistance to TNF cytotoxicity, and anti-TNF antibodies significantly decreased LPS-induced liver injury in knockout mice, indicating that the loss of autophagy sensitized to TNF-dependent liver damage. Hepatocyte autophagy, therefore, protects against LPS-induced liver injury. Conditions such as aging and steatosis that impair hepatic autophagy may predispose to poor outcomes from sepsis through this mechanism.

Decreased Macrophage Autophagy Promotes Liver Injury and Inflammation from Alcohol

“…Mice were then randomized to receive a 5% liquid ethanol diet (ED) (#F1258SP; Bio‐Serv) or pair‐fed an equal caloric amount of the CD for 21 days. On the final day of feeding, some mice received a single intraperitoneal injection of LPS (7.5 mg/kg; E. coli 0111:B4; Sigma, St. Louis, MO) as previously described (Lalazar et al., ). Mice were sacrificed at 6 hours after LPS injection for analysis.…”

Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock

“…Our study further delineates the role of autophagy genes in fatal systemic responses to TNF. Previous studies have demonstrated a protective role for genes regulating multiple steps of the autophagy pathway in different tissues of mice challenged with lipopolysaccharide (LPS)/endotoxin, including Atg7 in liver and kidney (66)(67)(68) and Becn1 and Rubicon in heart (69,70). A protective role for Atg7 and Atg16l1 in the myeloid compartment during endotoxin shock has also been demonstrated (71,72).…”

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

“…If some exogenous stimuli such as microbial invasion of the body insult the occurrence of endotoxemia, autophagy could trigger cell death pathways to protect or adapt the response. Researchers have focused concentration on identifying small molecules acting as chaperones to stimulate or stabilize proteins that regulate autophagy [6]. There is evidence indicated that LPS can induce autophagy in macrophages and mice [7,8].…”