RESUMO
The complexity of the multiple mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD. We report that miR-33 is overexpressed in hepatocytes isolated from mice with NAFLD and demonstrate that its specific suppression in hepatocytes (miR-33 HKO ) improves multiple aspects of the disease, including insulin resistance, steatosis, and inflammation and limits the progression to non-alcoholic steatohepatitis (NASH), fibrosis and hepatocellular carcinoma (HCC). Mechanistically, we find that hepatic miR-33 deficiency reduces lipid biosynthesis and promotes mitochondrial fatty acid oxidation to reduce lipid burden in hepatocytes. Additionally, miR-33 deficiency improves mitochondrial function, reducing oxidative stress. In miR-33 deficient hepatocytes, we found an increase in AMPKα activation, which regulates several pathways resulting in the attenuation of liver disease. The reduction in lipid accumulation and liver injury resulted in decreased transcriptional activity of the YAP/TAZ pathway, which may be involved in the reduced progression to HCC in the HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach at different stages of NAFLD/NASH/HCC disease progression.
RESUMO
BACKGROUND: In inflammatory bowel disease (IBD), enhanced inflammatory activity in the gut is thought to increase the risk of bacterial translocation and endotoxemia. By searching for signs of endotoxin-signaling cascade activation, including augmented levels of endotoxin, lipopolysaccharide-binding protein (LBP), and soluble CD14 receptor (sCD14), this prospective study sought to establish whether endotoxemia could contribute to greater clinical activity of disease. METHODS: Concentrations of plasma endotoxin, LBP, sCD14, several cytokines, acute phase proteins and clinical activity indices were determined in 104 patients with Crohn's disease (CD) and 52 patients with ulcerative colitis (UC). RESULTS: Endotoxemia was present in 48% of the patients with CD and in 28% of the patients with UC. The mean LBP was higher in patients with active CD (23.1 +/- 13.7 microg/mL) and UC (21.4 +/- 10.9 microg/mL) than in healthy controls (7.2 +/- 1.8 microg/mL; P < 0.01). Elevated serum concentrations of endotoxin and LBP were even detected in patients with inactive CD. Among the patients with active IBD, those with higher endotoxin levels had the worst clinical activity scores and the highest LBP levels. Treatment normalized LBP concentrations, from 29.1 +/- 13.0 to 15.2 +/- 7.3 microg/mL; (P < 0.05) in active CD and from 21.7 +/- 9.8 to 13.6 +/- 5.7 microg/mL; (P < 0.01) in active UC, along with normalizing endotoxin and sCD14 plasma concentrations. CONCLUSIONS: Patients with IBD show increased serum levels of endotoxin, LBP and sCD14. This alteration correlates with disease activity, with normal levels recovered after treatment, although less completely in Crohn's disease, and parallels a rise in proinflammatory cytokines, suggesting a contribution of bacterial products to the inflammatory cascade in these patients.