Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/28409
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Steinberg, Gregory | - |
dc.contributor.author | Morrow, Marisa | - |
dc.date.accessioned | 2023-03-30T12:53:41Z | - |
dc.date.available | 2023-03-30T12:53:41Z | - |
dc.date.issued | 2023 | - |
dc.identifier.uri | http://hdl.handle.net/11375/28409 | - |
dc.description.abstract | Non-alcoholic fatty liver disease (NAFLD) prevalence is increasing concurrently with obesity, type 2 diabetes (T2D), and cardiovascular diseases (CVDs), with 1 in 4 people being affected. NAFLD is the leading cause of chronic liver disease globally and yet there are still no approved therapeutics for its treatment. NAFLD is characterized by excessive accumulation of hepatic lipids and represents a continuum of pathologies, including fatty liver, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis. The presence of NASH and hepatic fibrosis predict the risk of developing liver cirrhosis, hepatocellular carcinoma (HCC), and liver failure. In addition to these liver-related pathologies, NASH is also closely linked to the pathogenesis of obesity, T2D, and CVDs, the latter being the leading cause of death in NAFLD patients. It has thus become critical to develop new therapies for NASH. A known contributor to NASH is elevated liver de novo lipogenesis (DNL), which can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) sits upstream of ACC and generates acetyl-CoA and oxaloacetate from citrate. Whether inhibition of ACLY is effective for treating NASH is unknown. The studies in this dissertation describe the characterization of a new mouse model that replicates many of the pathological and molecular drivers of NASH in humans. In this model, genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation and fibrosis. Mendelian randomization analysis demonstrates that human variants that mimic reductions in ACLY, associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for the treatment of NASH and dyslipidemia. | en_US |
dc.language.iso | en | en_US |
dc.title | ATP-CITRATE LYASE AS A THERAPEUTIC TARGET IN NON-ALCOHOLIC STEATOHEPATITIS | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Medical Sciences | en_US |
dc.description.degreetype | Dissertation | en_US |
dc.description.degree | Doctor of Philosophy (PhD) | en_US |
dc.description.layabstract | A common link between obesity, type 2 diabetes, and heart disease is non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by an excessive build-up of fat in the liver. In some people, this leads to liver inflammation and scarring, a disease called non-alcoholic steatohepatitis (NASH). This can subsequently lead to liver cancer or liver failure. Due to the epidemics of obesity and type 2 diabetes, NAFLD is becoming the most common cause of liver disease in the world, with 1 in 4 people being affected. One way to potentially reduce the amount of fat in the liver is to simultaneously reduce the production, and increase the burning (oxidation), of fat. ATP-citrate lyase (ACLY) is a protein in the liver that becomes more abundant in those with NAFLD. It has been shown to be important for controlling fat metabolism, however, whether inhibiting its activity may be effective for reducing NAFLD and NASH is not yet known. This dissertation discusses the development of a new mouse model which mimics NAFLD in humans. It also evaluates whether inhibiting ACLY using genetics, or a drug called bempedoic acid reduces NAFLD and NASH in this mouse model. The studies described in this dissertation demonstrate that inhibiting ACLY reduces fat synthesis and increases fat burning and this lowers liver fat accumulation, inflammation, and fibrosis, suggesting that ACLY blockage may be a potential new way of treating NAFLD and NASH. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Morrow_Marisa_R_Jan2022_PhD.pdf | 37.56 MB | Adobe PDF | View/Open |
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.