The role of adiponectin and adiponectin multimers in fatty liver disease

Thien Nguyen (2010). The role of adiponectin and adiponectin multimers in fatty liver disease PhD Thesis, Diamantina Institute for Cancer, Immunology and Metabolic Medicine, The University of Queensland.

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Author Thien Nguyen
Thesis Title The role of adiponectin and adiponectin multimers in fatty liver disease
School, Centre or Institute Diamantina Institute for Cancer, Immunology and Metabolic Medicine
Institution The University of Queensland
Publication date 2010-02
Thesis type PhD Thesis
Supervisor A/Prof Graeme Macdonald
Dr Linda Fletcher
Total pages 251
Total colour pages 15
Total black and white pages 136
Subjects 11 Medical and Health Sciences
Abstract/Summary Fatty liver disease, as a consequence of obesity or continual alcohol consumption, is a major health problem in developed countries, contributing significantly to the increasing health burden. Non-alcoholic fatty liver disease, NAFLD, is associated with significant metabolic complications, notably insulin resistance and cardiovascular problems, while alcoholic liver disease (ALD) is a consequence of hazardous alcohol consumption over time. NAFLD and ALD are histologically indistinguishable, with a morphological spectrum ranging from steatosis to steatohepatitis and cirrhosis. Adiponectin is a hormone with insulin-sensitising and anti-inflammatory properties. A number of studies have shown a decrease in circulating adiponectin concentration in obesity, insulin-resistance, type 2 diabetes, hypertension, cardiovascular disease. Emerging data also suggests a role for adiponectin in the pathogenesis of non-alcoholic fatty liver disease, but there are limited studies in alcoholic liver disease. Adiponectin exists in serum in a number of different multimeric forms. High molecular weight (HMW) adiponectin, one of its multimeric isoforms, appears to play an important role in hepatic insulin sensitivity, which in turn is implicated in the pathogenesis of NAFLD. NAFLD is a complex metabolic disease and it is likely that interactions between environmental and genetic factors influence disease severity. Consumption of high levels of dietary fat has been known to be a major factor in the development of obesity, but fatty acid composition of dietary fat may be as important as the absolute amount of fat consumed in the pathogenesis of fatty liver disease. The effect of specific dietary fatty acids on adiponectin concentration is unclear. The effects of adiponectin are mediated by two recently identified receptors, adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). AdipoR2, in particular, is highly expressed in the liver, however the molecular mechanism of action and physiological role are unclear. Most studies to date have investigated the relationships between total serum adiponectin and NAFLD, the studies reported in this thesis were unique. We examined the relationship between adiponectin multimer and NAFLD and ALD. Total serum adiponectin and adiponectin multimer concentrations were correlated with disease severity. There were two control groups, a healthy control group and a liver disease control group, chronic hepatitis B (HBV). HBV was selected because unlike other liver disease like hepatitis C, steatosis is not a major feature and the disease process has not been implicated in insulin resistance. We found decreased circulating total serum adiponectin in liver biopsy proven NAFLD subjects, which confirmed previous reports. A novel finding of our studies was that adiponectin multimer and the ratio of HMW to total adiponectin were also significantly lower in patients with NAFLD. As previously reported the concentration of total serum adiponectin and its multimer was higher in healthy female control subjects compared to males. We found that female healthy controls had higher total adiponectin concentration, HMW adiponectin and HMW/total adiponectin ratio than male healthy controls. However, total adiponectin concentrations, its multimer, and HMW/total adiponectin ratio were similar in male and female subjects with liver disease. Further analysis showed that it was the concentration of HMW adiponectin and not the low molecular weight (LMW) multimers that was the determining factor in NAFLD subjects. A subsequent chapter examined the relationship between serum adiponectin and its multimers and the severity of liver disease, based on histological scoring of liver biopsies. There was a trend towards a negative relationship in NAFLD between all forms of adiponectin with severity of liver disease as assessed by the NASH CRN scoring system. When we used the Brunt scoring system to classify patients according to the presence or absence of NASH, patients with NASH were found to have a significantly lower total serum, HMW and LMW adiponectin and ratio of HMW to total adiponectin than those with less severe NAFLD. In addition, NAFLD patients with diabetes, particularly male subjects, had more severe liver injury than those without diabetes. The later chapters, (Chapters 5 and 6), investigated mouse models of fatty liver disease to further characterise the relationship between adiponectin measures and types of dietary fatty acids and alcohol consumption. In the dietary experiments, the specific effects of two high fat diets, with 36% w/w fat (59% calories, containing mainly saturated fatty acids) and 23% w/w fat (43% calories, containing mainly hydrogenated vegetable oil) were examined. The ratio of HMW to total adiponectin was significantly lower in the 23% fat diet compared to chow fed mice, but that adiponectin concentrations were unchanged in the mice fed a diet containing 36% fat. Hepatic adiponectin receptor 1 (AdipoR1) mRNA expression was increased in the mice fed 36% fat diet, however the reason for this was unclear. There was no significant difference in Adiponectin receptor 2 (AdipoR2) mRNA expression. Serum adiponectin showed no correlation with steatosis or total histological severity score. Chapter 6 examined the effects of alcohol. Mice were fed standard Lieber-DeCarli alcohol diets with and without added corn oil (a source of poly-unsaturated fatty acids (PUFAs)), as was the previously used 23% fat-containing diet with and without alcohol. These studies supported the notion of cofactor interaction (“two hits”) in the pathogenesis of liver injury. Fatty acids (contained in corn oil), or alcohol, individually did not alter serum levels of total adiponectin, HMW, LMW or the ratio of HMW to total adiponectin. However when these two factors were administered simultaneously, adiponectin and adiponectin multimer levels were significantly decreased. Interestingly, fat pad AdipoR1 and AdipoR2 mRNA were significantly lower in mice fed corn oil either with or without alcohol. PUFAs and not hydrogenated vegetable oil appeared to be necessary to produce this effect. In summary, exploring the relationship between adiponectin multimers, biochemical parameters and liver histology in human subjects as described in this thesis has provided insights into the role of adiponectin multimers in the pathogenesis of fatty liver disease. By using dietary interventions in mouse models, significant findings relating to co-toxic effects of dietary fat and alcohol on have provided insights into the factors contributing to reduced adiponectin concentrations, which appear to exacerbate the progression of disease. This project has added to the understanding of adiponectin biology, particularly in relation to fatty liver disease which will be useful in further studies investigating the possible use of adiponectin in the clinical setting.
Keyword adiponectin, adiponectin multimers, adiponectin receptors, non alcoholic fatty liver disease, steatohepatitis, alcoholic liver disease, hepatic histology.
Additional Notes 34, 43, 46, 53, 71, 72, 120, 121, 122, 124, 125, 164, 165, 195, 196

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