Roles of Sirtuin 1 Activity and Tomato Carotenoids in the Development of Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma
Cheng, Junrui.
2018
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Abstract: The
prevalence of non-alcoholic fatty liver disease (NAFLD) is positively associated with
the obesity epidemic and the risks for hepatocellular carcinoma (HCC), which is the
second most cause of cancer mortality worldwide. Sirtuin 1 (SIRT1) is a NAD+-dependent
deacetylase that has emerged as a key metabolic sensor that links environmental signals
to metabolic homeostasis, NAFLD, and ... read moreto metabolic syndrome-associated HCC. Previous
studies have shown that supplementation of tomato carotenoids, such as
apo-10ʼ-lycopenoic acid (ALA) which is an oxidized metabolite of
apo-10ʼ-lycopenal through lycopene cleavage by beta-carotene-9ʼ,
10ʼ-oxygenase, can increase the expression and activity of SIRT1 and impede the
development of NAFLD and HCC. However, whether tomato carotenoids protect against NAFLD
and HCC dependent on SIRT1 signaling is enigmatic, and the causality between SIRT1
activity and the pathogenesis of NAFLD and HCC remains unknown. The primary objective of
this thesis is to investigate the causal role of systemic SIRT1 activity in the
development of NAFLD and HCC, and whether dietary tomato and tomato carotenoids, such as
ALA, protect against NAFLD and HCC in a SIRT1-dependent manner. In the 1st project, by
utilizing SIRT1 homozygous mutation mice ablated of the catalytic activity of SIRT1 (MT)
and their corresponding wild type (WT) littermates, we showed that SIRT1
loss-of-function aggravated high fat diet (HFD)-induced NAFLD progression, intriguingly,
by promoting the mobility of free fatty acid (FFA) from mesenteric adipose tissue (MAT)
to the liver. This study revealed a critical role of SIRT1 in preventing NAFLD, and
addressed the underlying mechanism that people without ʽbelly fatʼ still
develop fatty liver when SIRTt1 activity decreases due to certain factors such as aging,
unhealthy diet, or stress. In the 2nd project, both WT and MT mice were treated with
hepatic carcinogen diethylnitrosamine, followed by HFD feeding with or without tomato
powder (TP, representative of whole tomato) for 34 weeks. Results revealed that TP
supplementation significantly reduced liver steatosis in both WT and MT mice through
different molecular mechanisms. The protective effect of TP in WT mice was mediated by
increasing SIRT1 protein expression and activity, and decreasing hepatic fatty acid
binding protein 1 expression and FFA uptake. While in MT mice, TP decreased hepatic
fatty acid synthesis through inactivating hepatic acetyl-CoA carboxylase mediated by
AMPK phosphorylation, independent of SIRT1. Additionally, TP lowered il-6 mRNA
expression in MAT and IL-6 concentration in plasma, as compared with MT mice without TP.
In WT mice, dietary TP decreased caspase-1 mediated IL-1β maturation. However, we
did not detect significant hepatic inflammatory cell infiltration in both WT and MT
mice. Neither the mutation of SIRT1 activity nor TP supplementation altered incidence or
multiplicity of HCC in both WT and MT mice. This could be due to the lack of
inflammation as a target of TP protection or limited efficacy of SIRT1 in ameliorating
HCC development in this mouse model. Our final project demonstrated that ALA
supplementation at 10 mg/kg diet in WT and MT mice for 34 weeks achieved a comparable
effect against NAFLD between WT and MT mice. Unexpectedly, MT mice developed less
hepatic tumor multiplicity, as compared with WT mice fed the same dose of ALA.
Interestingly, the ablation of SIRT1 activity resulted in increased expression of
hepatic nuclear receptors (rxrα, lxrα, pparγ) and vitamin A
transporter cd36, and hepatic retinol concentration, but decreased cyclin D1 protein
levels, suggesting potential contribution of these nuclear receptors and retinol as well
as cell cycle arrest to the reduction of hepatic tumor multiplicity. This study
demonstrated that ALA protects against NAFLD and HCC independent of SIRT1 activity and
the lack of SIRT1 activity reduced the progression of HCC in mice given HFD and ALA
supplementation. In summary, through this thesis work, we first demonstrated the causal
role of absence of SIRT1 activity in the pathogenesis of NAFLD, which underscores the
key role of SIRT1 in ameliorating NAFLD progression through involving multiple organs.
Secondly by exploring an efficient dietary strategy against NAFLD, we demonstrated that
dietary TP as a whole food approach acts as an effective disease prevention strategy
against NAFLD independent of SIRT1 activity. Lastly, we demonstrated that lack of SIRT1
activity inhibited HCC development in mice given HFD and ALA supplementation,
highlighting the complex regulation of SIRT1 in hepatic tumorigenesis with paradoxical
functions as tumor suppressor or tumor
promoter.
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Xiang-dong Wang.
Committee: Lynne Ausman, Andrew Greenberg, and Dayong Wu.
Keywords: Nutrition, and Molecular biology.read less - ID:
- 3b591m968
- Component ID:
- tufts:24305
- To Cite:
- TARC Citation Guide EndNote
