Kupffer cells, the resident macrophages of the liver, play a major role in the pathogenesis of alcoholic liver disease. We have previously demonstrated that CB2 receptor protects against alcoholic liver disease by inhibiting alcohol-induced inflammation and steatosis via the regulation of Kupffer cell activation. Here, we explored the mechanism underlying these effects and hypothesized that the anti-inflammatory properties of CB2 receptor in Kupffer cells rely on activation of autophagy. For this purpose, mice invalidated for CB2 receptor (CB2^Mye−/− mice) or for the autophagy gene ATG5 (ATG5^Mye−/− mice) in the myeloid lineage and their littermate wild-type mice were subjected to chronic-plus-binge ethanol feeding. CB2^Mye−/− mice showed exacerbated alcohol-induced pro-inflammatory gene expression and steatosis. Studies in cultured macrophages demonstrated that CB2 receptor activation by JWH-133 stimulated autophagy via a heme oxygenase-1 dependent pathway. Moreover, JWH-133 reduced the induction of inflammatory genes by lipopolysaccharide in wild-type macrophages, but not in ATG5-deficient cells. The CB2 agonist also protected from alcohol-induced liver inflammation and steatosis in wild-type mice, but not in ATG5^Mye−/− mice demonstrating that macrophage autophagy mediates the anti-inflammatory and anti-steatogenic effects of CB2 receptor. Altogether these results demonstrate that CB2 receptor activation in macrophages protects from alcohol-induced steatosis by inhibiting hepatic inflammation through an autophagy-dependent pathway.

Failure to achieve sustained virological response (SVR) with hepatitis C virus (HCV) direct‐acting antiviral‐based regimens is commonly associated with emergence of resistance‐associated variants (RAVs). To avoid cross‐resistance, recent guidelines recommend that patients who have failed on nonstructural protein 5A (NS5A) inhibitors should be retreated with sofosbuvir (SOF; NS5B inhibitor) combined with simeprevir (SIM; protease inhibitor [PI]); however, supporting evidence is lacking. This “real‐world” study comprised patients who had failed to achieve SVR on previous NS5A‐based therapy with daclatasvir (DCV) plus pegylated interferon (Peg‐IFN) and ribavirin (RBV), with (n = 3) or without (n = 13) asunaprevir (ASV; PI). All 16 patients were retreated for 12 weeks with SOF plus SIM, without RBV. Antiviral efficacy was evaluated using the primary endpoint of SVR12 (SVR 12 weeks post‐treatment); on‐treatment response was also assessed. Patients (N = 16; 13 male; mean age: 54 years [range, 43‐73]) were chronically infected with HCV genotype (GT) 1 (1a, n = 11; 1b, n = 3) or 4 (n = 2); they had advanced fibrosis or compensated cirrhosis (FibroScan, 9.6‐70 kPa; cirrhosis, n = 9); median baseline HCV‐RNA level was 1.38 × 10⁶ IU/mL. No patient discontinued treatment because of adverse events or virological failure. All patients achieved HCV RNA below lower limit of quantification (<12 IU/mL) by end of treatment (EOT) and 10 of 16 had a rapid response (week 4). SVR12 was achieved by 14 of 16 patients; the remaining 2 relapsed by 4 weeks post‐EOT (both were GT 1a infected with cirrhosis; 1 had previously failed DCV‐ASV plus Peg‐IFN and RBV). Presence of SIM RAVs/polymorphisms (R155K and Q80K) at study baseline did not predict retreatment failure. Conclusion: Our findings support the concept of retreating NS5A inhibitor failures with SOF combined with SIM. However, the most difficult‐to‐cure patients may need more than 12 weeks of treatment and/or the addition of RBV. (Hepatology 2016;63:1809‐1816)