Comparative Effects of Fructose and Glucose on Lipogenic Gene Expression and Intermediary Metabolism in HepG2 Liver Cells

Consumption of large amounts of fructose or sucrose increases lipogenesis and circulating triglycerides in humans. Although the underlying molecular mechanisms responsible for this effect are not completely understood, it is possible that as reported for rodents, high fructose exposure increases expression of the lipogenic enzymes fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC-1) in human liver. Since activation of the hexosamine biosynthesis pathway (HBP) is associated with increases in the expression of FAS and ACC-1, it raises the possibility that HBP-related metabolites would contribute to any increase in hepatic expression of these enzymes following fructose exposure. Thus, we compared lipogenic gene expression in human-derived HepG2 cells after incubation in culture medium containing glucose alone or glucose plus 5 mM fructose, using the HBP precursor 10 mM glucosamine (GlcN) as a positive control. Cellular metabolite profiling was conducted to analyze differences between glucose and fructose metabolism. Despite evidence for the active uptake and metabolism of fructose by HepG2 cells, expression of FAS or ACC-1 did not increase in these cells compared with those incubated with glucose alone. Levels of UDP-N-acetylglucosamine (UDP-GlcNAc), the end-product of the HBP, did not differ significantly between the glucose and fructose conditions. Exposure to 10 mM GlcN for 10 minutes to 24 hours resulted in 8-fold elevated levels of intracellular UDP-GlcNAc (P<0.001), as well as a 74–126% increase in FAS (P<0.05) and 49–95% increase in ACC-1 (P<0.01) expression above controls. It is concluded that in HepG2 liver cells cultured under standard conditions, sustained exposure to fructose does not result in an activation of the HBP or increased lipogenic gene expression. Should this scenario manifest in human liver in vivo, it would suggest that high fructose consumption promotes triglyceride synthesis primarily through its action to provide lipid precursor carbon and not by activating lipogenic gene expression

Dietary Patterns and Cardiometabolic Disease Risk

ABSTRACT OF THE DISSERTATIONDietary Patterns and Cardiometabolic Disease RiskByKristin Michelle HirahatakeDoctor of Philosophy in Epidemiology University of California, Irvine, 2018 Assistant Professor Andrew Odegaard, Chair Diet was recently identified as the largest contributing risk factor across the leading causes of death in the United States. The nature of the diet-disease relationship based on the current body of evidence, however, remains inconclusive. The objective of this dissertation is to further explore the diet-disease relationship, specifically focusing on type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD). This dissertation consists of three separate research projects aiming to investigate the association between 1) contemporary national dietary guidelines and popular adapted dietary trends and 2) sweetened beverage consumption and T2D risk in young adults and 3) diet quality and CVD risk in postmenopausal women with prevalent T2D. In the first and second projects, prospective analyses of 4,627 young adults from the Coronary Artery Risk Development in Young Adults (CARDIA) study with repeated dietary histories were conducted to address the above aims. The first project examined the association between a priori dietary pattern scores created to reflect the 2015 Dietary Guidelines for Americans (2015 DGA) Scientific Report, a modern-day Paleolithic diet, low carbohydrate diet, CARDIA A Priori diet quality score and diet high in overall consumption of empty calories and T2D risk in young adults over time. The second project examined the association between artificially-sweetened beverage (ASB), sugar-sweetened beverage (SSB), and total sweetened beverage consumption and T2D risk in young adults in the CARDIA cohort over 30 years. For the third project, a prospective analysis of 5,809 postmenopausal women with prevalent T2D from the Women’s Health Initiative (WHI) was performed to study the relationship between diet quality as measured by four dietary pattern scores, an alternate Mediterranean (aMed), Dietary Approaches to Stop Hypertension (DASH), Paleolithic, and the American Diabetes Association (ADA) recommendations, and CVD risk over time. Multivariable Cox proportional hazards regression was used to characterize the prospective associations with incident T2D for the first two projects and incident CVD for the third project. Dietary pattern scores reflecting contemporary recommendations and popular patterns were not associated with T2D risk while the A Priori Diet Quality score, which largely aligns with the 2015 DGA, was strongly inversely associated with lower 30-year T2D risk in the CARDIA cohort. Additionally, long-term total-sweetened beverage consumption was associated with an increased risk of T2D, independent of diet quality, lifestyle factors, and BMI in this population; suggesting that whether or not they are causally related to T2D, higher intake of these beverages serves as a strong predictor of higher T2D risk in young adults. The aMed, DASH and ADA dietary patterns, emphasizing fruits, vegetables, whole grains, nuts/seeds, legumes and a high unsaturated:saturated fat ratio, were associated with a lower risk of incident CVD in postmenopausal women with T2D

Dietary Patterns and Cardiometabolic Disease Risk

ABSTRACT OF THE DISSERTATIONDietary Patterns and Cardiometabolic Disease RiskByKristin Michelle HirahatakeDoctor of Philosophy in Epidemiology University of California, Irvine, 2018 Assistant Professor Andrew Odegaard, Chair Diet was recently identified as the largest contributing risk factor across the leading causes of death in the United States. The nature of the diet-disease relationship based on the current body of evidence, however, remains inconclusive. The objective of this dissertation is to further explore the diet-disease relationship, specifically focusing on type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD). This dissertation consists of three separate research projects aiming to investigate the association between 1) contemporary national dietary guidelines and popular adapted dietary trends and 2) sweetened beverage consumption and T2D risk in young adults and 3) diet quality and CVD risk in postmenopausal women with prevalent T2D. In the first and second projects, prospective analyses of 4,627 young adults from the Coronary Artery Risk Development in Young Adults (CARDIA) study with repeated dietary histories were conducted to address the above aims. The first project examined the association between a priori dietary pattern scores created to reflect the 2015 Dietary Guidelines for Americans (2015 DGA) Scientific Report, a modern-day Paleolithic diet, low carbohydrate diet, CARDIA A Priori diet quality score and diet high in overall consumption of empty calories and T2D risk in young adults over time. The second project examined the association between artificially-sweetened beverage (ASB), sugar-sweetened beverage (SSB), and total sweetened beverage consumption and T2D risk in young adults in the CARDIA cohort over 30 years. For the third project, a prospective analysis of 5,809 postmenopausal women with prevalent T2D from the Women’s Health Initiative (WHI) was performed to study the relationship between diet quality as measured by four dietary pattern scores, an alternate Mediterranean (aMed), Dietary Approaches to Stop Hypertension (DASH), Paleolithic, and the American Diabetes Association (ADA) recommendations, and CVD risk over time. Multivariable Cox proportional hazards regression was used to characterize the prospective associations with incident T2D for the first two projects and incident CVD for the third project. Dietary pattern scores reflecting contemporary recommendations and popular patterns were not associated with T2D risk while the A Priori Diet Quality score, which largely aligns with the 2015 DGA, was strongly inversely associated with lower 30-year T2D risk in the CARDIA cohort. Additionally, long-term total-sweetened beverage consumption was associated with an increased risk of T2D, independent of diet quality, lifestyle factors, and BMI in this population; suggesting that whether or not they are causally related to T2D, higher intake of these beverages serves as a strong predictor of higher T2D risk in young adults. The aMed, DASH and ADA dietary patterns, emphasizing fruits, vegetables, whole grains, nuts/seeds, legumes and a high unsaturated:saturated fat ratio, were associated with a lower risk of incident CVD in postmenopausal women with T2D

Dietary Patterns and Cardiometabolic Disease Risk

Dietary Patterns and Cardiometabolic Disease Risk By Kristin Michelle Hirahatake Doctor of Philosophy in Epidemiology University of California, Irvine, 2018 Assistant Professor Andrew Odegaard, Chair Diet was recently identified as the largest contributing risk factor across the leading causes of death in the United States. The nature of the diet-disease relationship based on the current body of evidence, however, remains inconclusive. The objective of this dissertation is to further explore the diet-disease relationship, specifically focusing on type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD). This dissertation consists of three separate research projects aiming to investigate the association between 1) contemporary national dietary guidelines and popular adapted dietary trends and 2) sweetened beverage consumption and T2D risk in young adults and 3) diet quality and CVD risk in postmenopausal women with prevalent T2D. In the first and second projects, prospective analyses of 4,627 young adults from the Coronary Artery Risk Development in Young Adults (CARDIA) study with repeated dietary histories were conducted to address the above aims. The first project examined the association between a priori dietary pattern scores created to reflect the 2015 Dietary Guidelines for Americans (2015 DGA) Scientific Report, a modern-day Paleolithic diet, low carbohydrate diet, CARDIA a Priori diet quality score and diet high in overall consumption of empty calories and T2D risk in young adults over time. The second project examined the association between artificially-sweetened beverage (ASB), sugar-sweetened beverage (SSB), and total sweetened beverage consumption and T2D risk in young adults in the CARDIA cohort over 30 years. For the third project, a prospective analysis of 5,809 postmenopausal women with prevalent T2D from the Women’s Health Initiative (WHI) was performed to study the relationship between diet quality as measured by four dietary pattern scores, an alternate Mediterranean (aMed), Dietary Approaches to Stop Hypertension (DASH), Paleolithic, and the American Diabetes Association (ADA) recommendations, and CVD risk over time. Multivariable Cox proportional hazards regression was used to characterize the prospective associations with incident T2D for the first two projects and incident CVD for the third project. Dietary pattern scores reflecting contemporary recommendations and popular patterns were not associated with T2D risk while the a Priori Diet Quality score, which largely aligns with the 2015 DGA, was strongly inversely associated with lower 30-year T2D risk in the CARDIA cohort. Additionally, long-term total-sweetened beverage consumption was associated with an increased risk of T2D, independent of diet quality, lifestyle factors, and BMI in this population; suggesting that whether or not they are causally related to T2D, higher intake of these beverages serves as a strong predictor of higher T2D risk in young adults. The aMed, DASH and ADA dietary patterns, emphasizing fruits, vegetables, whole grains, nuts/seeds, legumes and a high unsaturated:saturated fat ratio, were associated with a lower risk of incident CVD in postmenopausal women with T2D