Dietary fat and cholesterol in the pathogenesis of obesity and non-alcoholic fatty liver disease
Creators: name: Li, Songpei
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 321099
subject: Nutrition and dietetics not elsewhere classified
classificationCode: 321401
subject: Basic pharmacology

description: The overall aim of this thesis was to investigate the role of dietary fat and cholesterol in the development of obesity, glucose intolerance and non-alcoholic fatty liver disease (NAFLD) and to investigate possible new mechanisms unravelled from the study.<br><br>Firstly, this thesis evaluated the metabolic characteristics of mice fed a high-fat (HF) diet and a moderate cholesterol diet (0.2% w/w), alone or in combination, for 17 weeks in light of the gaps of the current knowledge regarding the effect of cholesterol on obesity and related metabolic disorders. The results showed that chronic HF feeding induced obesity, glucose intolerance and simple hepatic steatosis but did not induce signs of non-alcoholic steatohepatitis (NASH). However, mice fed a combination of the HF diet with cholesterol displayed signs of liver injury and hepatic inflammation (indications of NASH) without the exacerbation of obesity and glucose intolerance. Mechanistic investigations suggest that dietary cholesterol may play a critical role in the transition from HF-induced hepatic steatosis towards NASH possibly by activating inflammation reactions within the liver. Furthermore, the study revealed, for the first time, cholesterol blunted mitochondrial function and this phenotype persisted after removing cholesterol from the HF diet.<br><br>The second part of thesis followed up this new finding of the sustained metabolic phenotype that has a similar feature to the “legacy effect” described in a long-term clinical trial. In this latter study, mice were intermittently fed two episodes of the HF diet with added cholesterol to induce metabolic preconditioning. Intriguingly, the results showed that the preconditioning was protective against obesity and glucose intolerance (but not fatty liver) during subsequent exposure to the same HF diet (with cholesterol) without decreasing calorie intake. Further investigation of the mechanisms underlying the amelioration of obesity showed a transformation of white adipose tissue towards brown adipose tissue (termed “browning”) as indicated by the expression of uncoupling protein 1, a specialised protein to promote energy expenditure as heat. There was an upregulation of some key proteins in the upstream pathway such as SIRT1 in the liver and plasma levels of FGF21 that are known to promote the “browning” of white adipose tissue. These findings suggest that preconditioning with a HF diet with cholesterol may exert “legacy effects” in lessening obesity and glucose intolerance possibly via increasing the capacity of energy expenditure of adipose tissue.<br><br>In summary, firstly, our studies suggest that cholesterol can precipitate asymptomatic hepatic steatosis towards NASH to worsen the outcome of NAFLD. Secondly, preconditioning may lessen the effects of the HF diet with cholesterol on obesity and glucose intolerance possibly via increasing the capacity of energy expenditure of adipose tissue. These findings provide a scientific rationale for a need of study in humans regarding the effect of combined dietary fat and cholesterol on obesity and NAFLD. Further investigation of the metabolic “legacy effects” may help develop new approaches for the prevention and treatment of obesity and associated metabolic disorders.