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Application of 5-oh polymethoxyflavones and safe mitochondrial uncouplers in preventing and treating type 2 diabetes and fatty liver diseases

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Title
Application of 5-oh polymethoxyflavones and safe mitochondrial uncouplers in preventing and treating type 2 diabetes and fatty liver diseases
Name (type = personal)
NamePart (type = family)
Guo
NamePart (type = given)
Jingjing
NamePart (type = date)
1990-
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Jingjing Guo
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author
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HUANG
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QINGRONG
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QINGRONG HUANG
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Advisory Committee
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chair
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CHI-TANG
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CHI-TANG HO
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Advisory Committee
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internal member
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Wu
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Qingli
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Qingli Wu
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Advisory Committee
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internal member
Name (type = personal)
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Jin
NamePart (type = given)
Shengkan
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Shengkan Jin
Affiliation
Advisory Committee
Role
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outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2019
DateOther (qualifier = exact); (type = degree)
2019-01
CopyrightDate (encoding = w3cdtf)
2019
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
In modern society, obesity-related metabolic diseases have become a serious public health concern globally. The increasing prevalence, disease progression, diverse complications and subsequent morbidity and mortality impose great medical challenges and socioeconomic burden. Type 2 diabetes (T2D) and nonalcoholic fatty liver diseases (NAFLD) are the two representative metabolic diseases. Current anti-diabetic medications only ameliorate diabetic symptoms but not effective in correcting the underlying causes of insulin resistance. Patients have to keep the medications for the rest of their lifetime. Nonalcoholic steatohepatitis (NASH) is an active form of NAFLD with no FDA-approved pharmacotherapy. Patients with NASH have higher risk of developing end-stage liver diseases including liver cirrhosis and hepatocellular carcinoma, and await liver transplantation to save life. The significant unmet medical needs of T2D and NAFLD call for therapeutics with novel working mechanisms. Excessive lipid accumulation is attributed to the underlying cause of multiple metabolic diseases, in particular T2D and NAFLD. At the same time, abnormal lipid deposition, particularly hepatic lipid accumulation, plays a fundamental role in the pathogenesis of some liver-based genetic disease such as lysosomal acid lipase deficiency (LAL-D), a genetic disease with profound lipid accumulation in liver.

The objective of my PhD research work is to identify novel nutraceuticals and pharmaceuticals that target lipid accumulation for treatment of T2D, NASH and LAL-D. My strategy is to target cellular metabolism to reduce intracellular lipid load. Depletion of fat accumulation corrected the causal factors of T2D and NASH as well as reduced the driving force of LAL-D disease progression. Our work on nutraceuticals focused on a group of 5-OH PMFs which presented promising therapeutic potential for the treatment of T2D and NAFL by targeting lipogenesis of adipogenesis. Our work on pharmaceuticals focused on a group of mitochondrial uncouplers which demonstrated strong therapeutic potential for the treatment of T2D, NASH and LAL-D by targeting hepatic lipid accumulation.

The first part of the work on nutraceuticals focused on the application of aged citrus peel (chenpi) extract as a novel nutraceutical for preventing obesity and T2D. Chenpi has long been used as an herbal medication and dietary supplement with excellent safety profile. Moreover, chenpi extract is uniquely enriched with 5-OH polymethoxyflavones (5-OH PMFs) compared to the fresh citrus peel extract. The chemical profile of chenpi extracts were quantitatively characterized. The therapeutic potential and underlying molecular mechanism of chenpi extract were systematically examined in relevant in vitro and in vivo models. The results demonstrated that 5-OH PMFs-enriched chenpi extract is effective to prevent high-fat diet induced obesity, insulin resistance, hyperglycemia, hypercholesterolemia and fatty liver in mice. And the beneficial effects of chenpi extract is attributed to the direct impact on lipid metabolism in adipocyte through activating AMPK pathway. A 5-OH PMFs content-dependent lipid-lowering efficacy of chenpi extract was also revealed.

Encouraged by the striking efficacy of 5-OH PMFs-enriched chenpi extract, the effect of casticin, a 5-OH PMF derivative, on lipid metabolism was investigated in differentiating adipocyte model. Casticin bears one extra hydroxyl group at 3’ position compared to its 5-OH PMF counterpart, 5-OH nobiletin. The results showed that casticin reduces intracellular lipid accumulation in differentiated adipocytes, which arises from the direct inhibition on cell proliferation and lipogenesis of adipogenesis. Moreover, casticin presents higher lipid-reducing efficacy and a different working mechanism compared to that of 5-OH nobiletin, which reveals a structure-activity relationship of 5-OH PMFs on suppressing adipogenesis.

Mitochondrial uncoupling is a biological process that efficiently stimulates lipid oxidation independent of ATP synthesis. Small chemicals that are capable of inducing mitochondrial uncoupling have emerged as a novel therapeutic approach to treat a myriad of diseases. However, how to improve the safety profile of the chemical uncouplers becomes the key obstacle of clinical translation of mitochondrial uncouplers strategy. In current work, we identified a group of safe mitochondrial uncouplers which induce mild mitochondrial uncoupling and specifically function in liver. Niclosamide ethanolamine (NEN) and niclosamide piperazine (NPP) are the two representative safe mitochondrial uncouplers exploited in current work. NEN and NPP, the salt forms of the FDA-approved drug, niclosamide, are bioavailable and have excellent safety profiles documented in mammals. When orally administrated, NEN and NPP distribute primarily to liver where they uncouple mitochondria of liver cells, which elevates lipid oxidation and reduces hepatic lipid load. We investigated the effect of NEN and NPP on treating obesity, T2D, NAFLD and LAL-D in relevant in vitro and in vivo models.

For treating obesity and T2D, oral administration of NPP effectively reduce the body weight gain and T2D symptoms through depletion of hepatic fat accumulation in HFD-induced obese/diabetic mouse model. For treating NAFLD and NASH, oral administration of NEN significantly reduces the hepatic steatosis, inflammation and fibrosis and improves the general metabolic profile in western diet-induced NASH mouse model. In addition, oral NEN treatment prevents and reverses CCl4 induced fibrosis in mice by directly inhibiting hepatic stellate cell activation. Overall, NEN-induced mitochondrial uncoupling targets hepatic steatosis and hepatic stellate cells activation, which accounts for its therapeutic potential of treating NASH. For treating LAL-D, oral NEN treatment significantly reduces hepatosplenomegaly, liver damage and dramatically prolongs the life span of lal-/- mice, suggesting the therapeutic potential of mitochondrial uncoupler for treating hepatic accumulation caused by gene mutations.

In summary, I developed chenpi extract and casticin as novel nutraceuticals and repurposed NEN and NPP as novel pharmacotherapies for treating T2D and NAFLD by targeting lipid metabolism. My work provided strong evidence that 5-OH PMFs-based nutraceuticals and safe mitochondrial uncouplers are promising therapeutic approaches for the treatment of T2D and fatty liver diseases.
Subject (authority = RUETD)
Topic
Food Science
Subject (authority = ETD-LCSH)
Topic
Non-insulin-dependent diabetes -- Prevention
Subject (authority = ETD-LCSH)
Topic
Lipids
Subject (authority = ETD-LCSH)
Topic
Fatty liver -- Prevention
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Rutgers University Electronic Theses and Dissertations
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1 online resource (150 pages : illustrations)
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Ph.D.
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Includes bibliographical references
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by Jingjing guo
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School of Graduate Studies Electronic Theses and Dissertations
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Identifier (type = doi)
doi:10.7282/t3-amhy-k725
Genre (authority = ExL-Esploro)
ETD doctoral
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The author owns the copyright to this work.
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Name
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Guo
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Jingjing
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2018-11-05 18:05:34
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Jingjing Guo
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Rutgers University. School of Graduate Studies
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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2019-01-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2021-01-30
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Access to this PDF has been restricted at the author's request. It will be publicly available after January 30th, 2021.
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