Mechanisms of glucagon-like peptide-1 in non-alcoholic fatty liver disease Öffentlichkeit

Mells, Jamie Eugene (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/5q47rp38v?locale=de
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Abstract

Mechanisms of glucagon-like peptide-1 in non-alcoholic fatty liver
disease

By

Jamie Eugene Mells
Non-alcoholic fatty liver disease (NAFLD) in developed nations is a significant disease burden,
but safe and effective medical therapy is still lacking. Glucagon-like peptide (GLP-1) is a
hormone secreted from L-cells in the distal ileum and colon. GLP-1 functions as an incretin
stimulating glucose-mediated insulin release from pancreatic β-cells. GLP-1 has additional
pleotropic functions in mammals including reduction in gastric emptying, inhibiting glucagon
secretion, increase satiety and induction of insulin mediated glucose uptake. At present, GLP-1
analogues, including Exendin-4 and Liraglutide , are currently being used in conjunction with
other pharmacotherapies for the treatment of type 2 diabetes mellitus. Previous studies performed
in our lab have shown that GLP-1 and Exendin-4 significantly reduced steatosis in the non-
alcoholic fatty livers of ob/ob mice and improve systemic insulin sensitivity. In addition we also
demonstrated that both GLP-1 and Exendin-4, increased cAMP production in rat hepatocytes, and
reduced mRNA expression of stearoyl-CoA desaturase 1 an enzyme involved in hepatic de novo
lipogenesis. Nonetheless, there is debate about whether GLP-1R receptors are present and
functional in human hepatocytes. The aims of this study were to 1) To characterize the cellular
interactions of GLP-1 in hepatocytes; 2) To characterize the normal and abnormal
pathways of hepatic lipid metabolism. The results from my study indicate that GLP-1R
is present in human hepatocytes, and is able to signal through key elements of the
signaling pathway including the phosphorylation of Akt, PDK-1 and PKC-ζ. In addition
we found that administering a Western diet causes hepatic insulin resistance that precedes
systemic insulin resistance in mice. In addition the diet caused hepatic steatosis, high
blood pressure and cardiac hypertrophy. GLP-1 analogues reduce lipid accumulation in
hepatocytes, by improving insulin sensitivity, and increasing the expression of critical
proteins involved in lipid transport, secretion and β-oxidation; which we hypothesize
reduce fat accumulation in the liver. GLP-1 analogues may provide an attractive alternative
for use as a medical therapy for NAFLD, particularly in diabetic patients or earlier forms of
insulin resistance.



Mechanisms of glucagon-like peptide-1 in non-alcoholic fatty liver
disease

By

Jamie Eugene Mells
M.S. Austin Peay State University, 2004
B.S. Austin Peay State University, 1996
A.A. University of Maryland, 1993
Advisor: Frank A. Anania, M.D.
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
In partial fulfillment of the requirements of the requirements for the degree of
Doctor of Philosophy in
Graduate Division of Biological and Biomedical Sciences,
Nutrition and Health Program, 2011

Table of Contents


Table of Contents

Chapter 1: Introduction ...................................................................................................... 1
Background and Significance .......................................................................................... 2
Obesity and Type II Diabetes ...................................................................................... 2
NAFLD: pathology-spectrum of disease .................................................................. 6
NAFLD Epidemiology ................................................................................................ 7
NAFLD--current hypotheses on development ............................................................ 7
NAFLD-emerging concept of free fatty acids and the concept of lipotoxicity ...... 10
Changes in Food Manufacturing and and it's relation to T2DM and NAFLD: Trans-
fatty acids and High Fructose Corn Syrup................................................................. 11
Treatment Strategies for NAFLD: targeting insulin resistance ................................ 13
Structure and Function of GLP-1 .............................................................................. 15
The role of GLP-1R: mechanisms of action .............................................................. 16
Rationale for Dissertation .............................................................................................. 17
Chapter 2: Glucagon-like Peptide-1 Receptor (GLP-1R) is present on human hepatocytes
and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the
insulin signaling pathway ................................................................................................. 20
Abstract ......................................................................................................................... 21
Background ................................................................................................................... 22
Materials and Methods .................................................................................................. 24
Results ........................................................................................................................... 28
Discussion ..................................................................................................................... 40
Chapter 3: GLP-1 analogue, liraglutide ameliorates hepatic steatosis and cardiac
hypertrophy in C57BL/6J mice fed a western diet. .......................................................... 48
Abstract ......................................................................................................................... 49
Background ................................................................................................................... 51
Research Design and Methods ...................................................................................... 52
Results ........................................................................................................................... 57
Discussion ..................................................................................................................... 81
Chapter 4: Conclusions and Future Directions ................................................................. 87

Conclusion Summary .................................................................................................... 88
Novel findings ............................................................................................................... 88
Future Aims ................................................................................................................... 92
Additional Questions ..................................................................................................... 95
References: ........................................................................................................................ 97





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