Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide.Its pathogenesis is complex and not yet fully understood.Over the years many studies have proposed various pathophysiological ...Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide.Its pathogenesis is complex and not yet fully understood.Over the years many studies have proposed various pathophysiological hypotheses,among which the currently most widely accepted is the"multiple parallel hits"theory.According to this model,lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury,inflammation and fibrosis.Among these factors,adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role.Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue,and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD.Furthermore,given the strong association between these conditions,current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD.The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction,and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity,together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD.展开更多
The pathogenesis of liver damage associated with chronic hepatitis C virus （HCV） infection is thought to be largely immunomediated. However, some frequent histoo pathological features, such as steatosis, suggest a d...The pathogenesis of liver damage associated with chronic hepatitis C virus （HCV） infection is thought to be largely immunomediated. However, some frequent histoo pathological features, such as steatosis, suggest a direct cytopathic effect of HCV. The direct responsibility of HCV in the pathogenesis of steatosis is shown by： （1） the association with HCV genotype 3 infection, suggesting that some viral sequences are involved in the intracellular aco cumulation of lipids; （2） the correlation between severity of steatosis and HCV replication levels; （3） association between response to treatment and disappearance of steatosis. Experimental studies have shown that the nuo cleocapsid protein of HCV （core protein） is capable and sufficient to induce lipid accumulation in hepatocytes. Moreover, the observation that chronic hepatitis C pao tients have reduced serum levels of ApoB suggests an interference with the very-low density lipoprotein （VLDL） assembly, although other mechanisms are possible. In patients with sustained virological response induced by antiviral therapy, such levels are normalized. Other obo servations suggest that the pathogenesis of steatosis in chronic hepatitis C is not solely due to HCV. The origin of the mild steatosis observed in most patients may be metabolic, since its severity correlates with body mass index and insulin resistance. Most studies have shown a correlation between presence and/or severity of steatosis and fibrosis stage, but it is unclear whether this effect is direct or mediated by the associated insulin resistance, increased susceptibility to apoptosis, or by inflammao tory cytokines. Finally, steatosis negatively influences the rate of response to antiviral treatment, as confirmed by large clinical trials. Management of steatosis in chronic hepatitis C requires knowledge of its pathogenesis and may involve both life-style changes and pharmacological interventions, although the latter remain largely experio mental.展开更多
Chronic hepatitis due to any cause leads to cirrhosis and end-stage liver disease.A growing body of literature has also shown that fatty liver due to overweight or obesity is a leading cause of cirrhosis.Due to the ob...Chronic hepatitis due to any cause leads to cirrhosis and end-stage liver disease.A growing body of literature has also shown that fatty liver due to overweight or obesity is a leading cause of cirrhosis.Due to the obesity epidemic,fatty liver is now a significant problem in clinical practice.Steatosis has an impact on the acceleration of liver damage in patients with chronic hepatitis due to other causes.An association between hepatitis C virus (HCV) infection,steatosis and the onset of insulin resistance has been reported.Insulin resistance is one of the leading factors for severe fibrosis in chronic HCV infections.Moreover,hyperinsulinemia has a deleterious effect on the management of chronic HCV.Response to therapy is increased by decreasing insulin resistance by weight loss or the use of thiazolidenediones or metformin.The underlying mechanisms of this complex interaction are not fully understood.A direct cytopathic effect of HCV has been suggested.The genomic structure of HCV (suggesting that some viral sequences are involved in the intracellular accumulation of triglycerides),lipid metabolism,the molecular links between the HCV core protein and lipid droplets (the core protein of HCV and its transcriptional regulatory function which induce a triglyceride accumulation in hepatocytes) and increased neolipogenesis and inhibited fatty acid degradation in mitochondria have been investigated.展开更多
AIM:To ascertain whether carotid lesions are more prevalent in outpatients with incidental findings of nonalcoholic fatty liver disease (NAFLD) at abdominal ultrasound (US).METHODS: One hundred and fifty-four consecut...AIM:To ascertain whether carotid lesions are more prevalent in outpatients with incidental findings of nonalcoholic fatty liver disease (NAFLD) at abdominal ultrasound (US).METHODS: One hundred and fifty-four consecutive outpatients (age range 24-90 years, both sexes) referred by general practitioners for abdominal US, and drinking less than 20 g alcohol/day, underwent carotid US for an assessment of carotid intima-media thickness (c-IMT) and carotid plaque prevalence. Hepatic steatosis, visceral fat thickness and subcutaneous fat thickness were also assessed at ultrasonography.RESULTS: Higher c-IMT values were found in the presence of NAFLD (90 patients), even after adjustment for indices of general and abdominal obesity and for the principal cardiovascular risk factors (0.84±0.10 mm vs 0.71±0.10 mm, P<0.001). The prevalence of carotid plaques was 57.8% in the patients with NAFLD vs 37.5% in the patients without this condition (P=0.02). The adjusted relative risk of having carotid plaques for patients with NAFLD was 1.85 (95% CI:1.33-2.57, P<0.001).CONCLUSION: An incidental finding of hepatic steatosis may suggest the presence of silent carotid atherosclerotic lesions.展开更多
AIM To determine if manipulation of dietary advanced glycation end product(AGE), intake affects nonalcoholic fatty liver disease(NAFLD) progression and whether these effects are mediated via RAGE. METHODS Male C57Bl6 ...AIM To determine if manipulation of dietary advanced glycation end product(AGE), intake affects nonalcoholic fatty liver disease(NAFLD) progression and whether these effects are mediated via RAGE. METHODS Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol(HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mR NA were determined. RESULTS Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content(a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE-/-animals developed NASH of similar severity to RAGE+/+ animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.展开更多
文摘Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide.Its pathogenesis is complex and not yet fully understood.Over the years many studies have proposed various pathophysiological hypotheses,among which the currently most widely accepted is the"multiple parallel hits"theory.According to this model,lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury,inflammation and fibrosis.Among these factors,adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role.Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue,and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD.Furthermore,given the strong association between these conditions,current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD.The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction,and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity,together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD.
基金Supported by the Swiss National Science Foundation grant, No. 3200B0-103727/1
文摘The pathogenesis of liver damage associated with chronic hepatitis C virus （HCV） infection is thought to be largely immunomediated. However, some frequent histoo pathological features, such as steatosis, suggest a direct cytopathic effect of HCV. The direct responsibility of HCV in the pathogenesis of steatosis is shown by： （1） the association with HCV genotype 3 infection, suggesting that some viral sequences are involved in the intracellular aco cumulation of lipids; （2） the correlation between severity of steatosis and HCV replication levels; （3） association between response to treatment and disappearance of steatosis. Experimental studies have shown that the nuo cleocapsid protein of HCV （core protein） is capable and sufficient to induce lipid accumulation in hepatocytes. Moreover, the observation that chronic hepatitis C pao tients have reduced serum levels of ApoB suggests an interference with the very-low density lipoprotein （VLDL） assembly, although other mechanisms are possible. In patients with sustained virological response induced by antiviral therapy, such levels are normalized. Other obo servations suggest that the pathogenesis of steatosis in chronic hepatitis C is not solely due to HCV. The origin of the mild steatosis observed in most patients may be metabolic, since its severity correlates with body mass index and insulin resistance. Most studies have shown a correlation between presence and/or severity of steatosis and fibrosis stage, but it is unclear whether this effect is direct or mediated by the associated insulin resistance, increased susceptibility to apoptosis, or by inflammao tory cytokines. Finally, steatosis negatively influences the rate of response to antiviral treatment, as confirmed by large clinical trials. Management of steatosis in chronic hepatitis C requires knowledge of its pathogenesis and may involve both life-style changes and pharmacological interventions, although the latter remain largely experio mental.
文摘Chronic hepatitis due to any cause leads to cirrhosis and end-stage liver disease.A growing body of literature has also shown that fatty liver due to overweight or obesity is a leading cause of cirrhosis.Due to the obesity epidemic,fatty liver is now a significant problem in clinical practice.Steatosis has an impact on the acceleration of liver damage in patients with chronic hepatitis due to other causes.An association between hepatitis C virus (HCV) infection,steatosis and the onset of insulin resistance has been reported.Insulin resistance is one of the leading factors for severe fibrosis in chronic HCV infections.Moreover,hyperinsulinemia has a deleterious effect on the management of chronic HCV.Response to therapy is increased by decreasing insulin resistance by weight loss or the use of thiazolidenediones or metformin.The underlying mechanisms of this complex interaction are not fully understood.A direct cytopathic effect of HCV has been suggested.The genomic structure of HCV (suggesting that some viral sequences are involved in the intracellular accumulation of triglycerides),lipid metabolism,the molecular links between the HCV core protein and lipid droplets (the core protein of HCV and its transcriptional regulatory function which induce a triglyceride accumulation in hepatocytes) and increased neolipogenesis and inhibited fatty acid degradation in mitochondria have been investigated.
基金Supported by (in part) A grant from Gruppo Italiano di Ultrasonologia in Medicina Interna (GIUMI)
文摘AIM:To ascertain whether carotid lesions are more prevalent in outpatients with incidental findings of nonalcoholic fatty liver disease (NAFLD) at abdominal ultrasound (US).METHODS: One hundred and fifty-four consecutive outpatients (age range 24-90 years, both sexes) referred by general practitioners for abdominal US, and drinking less than 20 g alcohol/day, underwent carotid US for an assessment of carotid intima-media thickness (c-IMT) and carotid plaque prevalence. Hepatic steatosis, visceral fat thickness and subcutaneous fat thickness were also assessed at ultrasonography.RESULTS: Higher c-IMT values were found in the presence of NAFLD (90 patients), even after adjustment for indices of general and abdominal obesity and for the principal cardiovascular risk factors (0.84±0.10 mm vs 0.71±0.10 mm, P<0.001). The prevalence of carotid plaques was 57.8% in the patients with NAFLD vs 37.5% in the patients without this condition (P=0.02). The adjusted relative risk of having carotid plaques for patients with NAFLD was 1.85 (95% CI:1.33-2.57, P<0.001).CONCLUSION: An incidental finding of hepatic steatosis may suggest the presence of silent carotid atherosclerotic lesions.
基金Supported by National Health and Medical Research Council of AustraliaNHMRC early career fellowship
文摘AIM To determine if manipulation of dietary advanced glycation end product(AGE), intake affects nonalcoholic fatty liver disease(NAFLD) progression and whether these effects are mediated via RAGE. METHODS Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol(HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mR NA were determined. RESULTS Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content(a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE-/-animals developed NASH of similar severity to RAGE+/+ animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.
