American Journal of Physiology-gastrointestinal and Liver Physiology, Jul 1, 1996
In this study, we investigated the effects of a glycine-containing diet (5%) on mortality and liv... more In this study, we investigated the effects of a glycine-containing diet (5%) on mortality and liver injury due to intravenous injection of endotoxin [Escherichia coli lipopolysaccharide (LPS)] in Sprague-Dawley rats in vivo. Fifty percent of the rats fed control diet died within 24 h after an intravenous injection of LPS (10 mg/kg), whereas feeding the rats glycine totally prevented mortality and markedly reduced an LPS-induced elevation of serum transaminase levels, hepatic necrosis, and lung injury. The elevation in serum tumor necrosis factor-alpha (TNF-alpha) due to LPS was also blunted and delayed significantly by glycine feeding. In a two-hit model (hepatic ischemia-reperfusion and injection of sublethal LPS), all rats fed control diet died, whereas 83% of glycine-fed animals survived with a significant reduction in transaminases and improved liver and lung histology. LPS elevated intracellular Ca2+ concentration ([Ca2+]i) in cultured Kupffer cells, an effect blocked almost completely by glycine. Glycine most likely reduces injury and mortality by preventing the LPS-induced elevation of [Ca2+]i in Kupffer cells, thereby minimizing toxic eicosanoid and cytokine production.
AimRecent evidences indicate that hepatic steatosis suppresses autophagic proteolysis. The presen... more AimRecent evidences indicate that hepatic steatosis suppresses autophagic proteolysis. The present study evaluated the correlation between autophagic function and cathepsin expression in the liver from patients with non‐alcoholic fatty liver disease (NAFLD).MethodsLiver biopsy specimens were obtained from patients with chronic liver diseases (chronic hepatitis C [CHC; n = 20], chronic hepatitis B [CHB; n = 16], primary biliary cirrhosis [PBC; n = 23], NAFLD [n = 22] and control [n = 14]). The number of autophagic vesicles in hepatocytes was counted by using transmission electron microscopy. Expression of cathepsin B, D, L and p62 in the liver section was analyzed by immunohistochemical staining. The histological severity of NAFLD is assessed by NAFLD activity score (NAS).ResultsThe number of autophagic vesicles in hepatocytes was significantly increased in both CHC and NAFLD groups, but not CHB and PBC, more than control. Although hepatocytes with aggregation of p62 were observed in less than 15% of CHC, p62 aggregation was detected in approximately 65% of NAFLD. Cathepsin B, D and L expression was significantly suppressed in the liver from NAFLD patients. Suppression of cathepsin B, D and L expression was not observed in CHB, CHC and PBC. In NAFLD patients, p62 aggregation was correlated with serum alanine aminotransferase value and inflammatory activity by NAS.ConclusionThese results indicate that a decrease in hepatic cathepsin expression in NAFLD is associated with autophagic dysfunction. Hepatic inflammation correlates with autophagic dysfunction in NAFLD. These findings indicate that the suppression of autophagic proteolysis by hepatic steatosis is involved in the pathogenesis of NAFLD.
A S L D A b st ra ct s and liver cholesterol levels were measured. We compared gene expression pr... more A S L D A b st ra ct s and liver cholesterol levels were measured. We compared gene expression profiles of liver specimen from MCD diet fed mice with those from MCS diet fed mice, and examined the effect of exendin-4 on gene expression profiles in the liver on MCD diet fed mice, using Agilent whole mouse genome oligo microarrays (Agilent Technologies). We also performed a cholesterol biosynthesis pathway analysis significantly affected transcripts of the liver. Results: While serum cholesterol levels were significantly decreased by MCD diet, exendin4 had a tendency to decrease serum cholesterol levels. On the other hand, hepatic cholesterol levels were significantly increased by MCD diet compared with those by MCS diet. Exendin4 significantly decreased MCD diet-induced increase of hepatic cholesterol levels compared with saline. Transcripts for 6476 mRNAs differed in expression patterns > 2 fold between MCS diet and MCD diet with saline groups. Furthermore, transcripts for 7740 mRNAs differed in expression patterns > 2 fold between MCD diet with saline groups and MCD diet with exendin-4. The pathway of gene expressions most impacted by MCD diet was cholesterol biosynthesis. MCD diet up-regulated cholesterol biosynthesis signaling. In contrast, exendin-4 down-regulated cholesterol biosynthesis signaling. Conclusions: Exendin4 inhibited MCD diet-induced increase of hepatic cholesterol levels through the inhibition of cholesterol biosynthesis. These results indicate that exendin-4 may decrease hepatic cholesterol resulting in the attenuation of hepatic inflammation in NASH model.
American Journal of Physiology-gastrointestinal and Liver Physiology, Jul 1, 1996
In this study, we investigated the effects of a glycine-containing diet (5%) on mortality and liv... more In this study, we investigated the effects of a glycine-containing diet (5%) on mortality and liver injury due to intravenous injection of endotoxin [Escherichia coli lipopolysaccharide (LPS)] in Sprague-Dawley rats in vivo. Fifty percent of the rats fed control diet died within 24 h after an intravenous injection of LPS (10 mg/kg), whereas feeding the rats glycine totally prevented mortality and markedly reduced an LPS-induced elevation of serum transaminase levels, hepatic necrosis, and lung injury. The elevation in serum tumor necrosis factor-alpha (TNF-alpha) due to LPS was also blunted and delayed significantly by glycine feeding. In a two-hit model (hepatic ischemia-reperfusion and injection of sublethal LPS), all rats fed control diet died, whereas 83% of glycine-fed animals survived with a significant reduction in transaminases and improved liver and lung histology. LPS elevated intracellular Ca2+ concentration ([Ca2+]i) in cultured Kupffer cells, an effect blocked almost completely by glycine. Glycine most likely reduces injury and mortality by preventing the LPS-induced elevation of [Ca2+]i in Kupffer cells, thereby minimizing toxic eicosanoid and cytokine production.
AimRecent evidences indicate that hepatic steatosis suppresses autophagic proteolysis. The presen... more AimRecent evidences indicate that hepatic steatosis suppresses autophagic proteolysis. The present study evaluated the correlation between autophagic function and cathepsin expression in the liver from patients with non‐alcoholic fatty liver disease (NAFLD).MethodsLiver biopsy specimens were obtained from patients with chronic liver diseases (chronic hepatitis C [CHC; n = 20], chronic hepatitis B [CHB; n = 16], primary biliary cirrhosis [PBC; n = 23], NAFLD [n = 22] and control [n = 14]). The number of autophagic vesicles in hepatocytes was counted by using transmission electron microscopy. Expression of cathepsin B, D, L and p62 in the liver section was analyzed by immunohistochemical staining. The histological severity of NAFLD is assessed by NAFLD activity score (NAS).ResultsThe number of autophagic vesicles in hepatocytes was significantly increased in both CHC and NAFLD groups, but not CHB and PBC, more than control. Although hepatocytes with aggregation of p62 were observed in less than 15% of CHC, p62 aggregation was detected in approximately 65% of NAFLD. Cathepsin B, D and L expression was significantly suppressed in the liver from NAFLD patients. Suppression of cathepsin B, D and L expression was not observed in CHB, CHC and PBC. In NAFLD patients, p62 aggregation was correlated with serum alanine aminotransferase value and inflammatory activity by NAS.ConclusionThese results indicate that a decrease in hepatic cathepsin expression in NAFLD is associated with autophagic dysfunction. Hepatic inflammation correlates with autophagic dysfunction in NAFLD. These findings indicate that the suppression of autophagic proteolysis by hepatic steatosis is involved in the pathogenesis of NAFLD.
A S L D A b st ra ct s and liver cholesterol levels were measured. We compared gene expression pr... more A S L D A b st ra ct s and liver cholesterol levels were measured. We compared gene expression profiles of liver specimen from MCD diet fed mice with those from MCS diet fed mice, and examined the effect of exendin-4 on gene expression profiles in the liver on MCD diet fed mice, using Agilent whole mouse genome oligo microarrays (Agilent Technologies). We also performed a cholesterol biosynthesis pathway analysis significantly affected transcripts of the liver. Results: While serum cholesterol levels were significantly decreased by MCD diet, exendin4 had a tendency to decrease serum cholesterol levels. On the other hand, hepatic cholesterol levels were significantly increased by MCD diet compared with those by MCS diet. Exendin4 significantly decreased MCD diet-induced increase of hepatic cholesterol levels compared with saline. Transcripts for 6476 mRNAs differed in expression patterns > 2 fold between MCS diet and MCD diet with saline groups. Furthermore, transcripts for 7740 mRNAs differed in expression patterns > 2 fold between MCD diet with saline groups and MCD diet with exendin-4. The pathway of gene expressions most impacted by MCD diet was cholesterol biosynthesis. MCD diet up-regulated cholesterol biosynthesis signaling. In contrast, exendin-4 down-regulated cholesterol biosynthesis signaling. Conclusions: Exendin4 inhibited MCD diet-induced increase of hepatic cholesterol levels through the inhibition of cholesterol biosynthesis. These results indicate that exendin-4 may decrease hepatic cholesterol resulting in the attenuation of hepatic inflammation in NASH model.
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