Effects of Increased Dietary High-Fructose Corn Syrup on Intrahepatic Triglyceride Content and Lipoprotein Kinetics in People with a Non-Alcoholic Fatty Liver Disease

Shelby Sullivan, M.D.


Project Overview:
Nonalcoholic fatty liver disease (NAFLD) is a common medical problem in the United States. It is a disease of too much fat being stored in the liver, which can in some cases lead to damage in the liver itself. In addition, NAFLD is associated with obesity, and 33% of the adult population in the U.S. has NAFLD. This is a problem not only because of the effect of NAFLD on the liver, but also because NAFLD is associated with serious medical complications including diabetes, high blood pressure, high triglycerides and death from heart attacks.

Information from recent studies shows that the fructose (a type of sugar) in high-fructose corn syrup (HFCS) plays a role in the development of NAFLD. HFCS is made from corn, which is found throughout the U.S. food supply, and accounts for 40%-50% of the added sugars eaten in the U.S. It appears that when HFCS is eaten in large amounts, even by people with normal livers, it may cause the liver to use HFCS to make fat, a process known as de novo lipogenesis. The liver can remove fat by either using it as energy or by secreting it in very low density lipoprotein particles. However both of these processes have an upper limit, and when that limit is reached, the fat must be stored. Therefore, the fat that is produced from de novo lipogenesis due to consuming HFCS may be more than the liver can use or secrete and is stored, leading to NAFLD. Unfortunately, most studies have over-fed people with fructose, and over-feeding by itself can cause de novo lipogenesis. Furthermore, no studies have directly measured the effect of eating a weight-stable diet high in HFCS on liver fat in persons with NAFLD, and therefore it is unknown what the effects of a weight-stable diet high in HFCS will be in persons with NAFLD.

The objectives of this proposal are to measure the effects of consuming a weight-stable diet high in HFCS in obese people with NAFLD on: 1) liver fat content; 2) liver fat metabolism; and 3) insulin sensitivity. We will measure these items with the following tests:

Liver fat content: we will measure by magnetic resonance spectroscopy.

  • Hyposthesis 1. We believe that a weight stable diet high in HFCS will cause liver fat to increase.
    Liver fat metabolism (de novo lipogenesis, very low density lipoprotein secretion rates) will be measured using stable isotope tracer methods. 
  • Hypothesis 2. We believe a weight-stable diet high in HFCS will cause an increase in de novo lipogenesis and increase very low density lipoprotein secretion out of the liver.
    Insulin sensitivity will be measured by using a hyperinsulinemic euglycemic clamp procedure in which insulin and glucose (a sugar) are given intravenously to determine insulin sensitivity in liver and muscle.
  • Hypothesis 3. We believe that feeding obese subjects with NAFLD a weight-stable diet high in HFCS will cause a decrease in insulin sensitivity in the liver, which causes the liver to make more glucose than it should; and a decrease in skeletal muscle insulin sensitivity, which is the amount of glucose that muscle cells take in to use for energy.

The results of this study will lay the groundwork for determining what role HFCS plays in the development of NAFLD – whether it only worsens the disease once it is present, or if it actually causes the disease. Our group has substantial experience with these types of metabolic studies to measure metabolic events in humans. Furthermore, we have perfected a method for measuring liver fat with magnetic resonance spectroscopy, a type of MRI.


Longer Life Foundation: Final Report

 Abstract:
The objectives of this proposal are to measure the effects of consuming a weight-stable diet high in high-fructose corn syrup (HFCS) in obese people with NAFLD on 1) liver fat content using magnetic resonance spectroscopy, 2) liver fat metabolism using stable isotope tracer methods, and 3) insulin sensitivity using the hyperinsulinemic-euglycemic clamp technique. I am pleased to report that although the study is far from complete, the Longer Life Foundation Developmental Research Award helped me to secure a K23 Mentored Career Development Award from the National Institutes of Health. First, the comments from the Review Committee helped me to alter my protocol in order to better answer the clinical questions I set out to answer in my research objectives. Second, the small amount of data I submitted with my application suggests that a weight-stable diet high in HFCS does increase blood lipids in obese people with nonalcoholic fatty liver disease. The K23 Mentored Career Development Award will fund my salary and my research for three years, and will allow me to compete for an R01 award to become an independent physician scientist.

 Lay Summary:
Nonalcoholic fatty liver disease (NAFLD) is a common medical problem in the United States. It is a disease of too much fat being stored in the liver, which can in some cases lead to damage to the liver itself. In addition, NAFLD is associated with obesity, and 33% of the adult population in the U.S. has NAFLD. This is a problem not only because of the effect of NAFLD on the liver, but also because NAFLD is associated with serious medical complications including diabetes, high blood pressure, high triglycerides and death from heart attacks. Information from recent studies suggest that fructose, in the form of high fructose corn syrup (HFCS), plays a role in the development of NAFLD, regardless of how many calories are eaten.

HFCS is made from corn, and is composed of fructose and glucose. It is found throughout the U.S. food supply, and accounts for 40%-50% of the added sugars eaten in the U.S. It appears that when HFCS is eaten in large amounts even by people with normal livers, it may cause the liver to use the HFCS to make fat, a process known as de novo lipogenesis. The liver can remove fat by either using it as energy or by secreting it in very low-density lipoprotein particles.

However, both of these processes have an upper limit, and when that limit is reached, the fat must be stored. Therefore, the fat that is produced from de novo lipogenesis from the consumption of HFCS may be more than the liver can use or secrete and is stored, leading to NAFLD. Unfortunately, most studies have overfed participants with fructose, and overfeeding by itself can cause de novo lipogenesis. Furthermore, no studies have directly measured the effect of eating a weight-stable diet high in HFCS on liver fat in persons with NAFLD, and therefore it is unknown what the effects of a weight-stable diet high in HFCS will be in persons with NAFLD.

The objectives of this proposal are to compare the effects of consuming a weight-stable diet high in HFCS with a diet low in HFCS in obese people with NAFLD and with a diet high in HFCS in obese people with normal liver fat on 1) liver fat content, 2) liver fat metabolism, and 3) insulin sensitivity.

 Introduction:
The proposed research focuses on a carbohydrate source that is prevalent in the U.S. food supply – high fructose corn syrup (HFCS) – and its role in the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD). NAFLD affects approximately one-third of the adult population in the U.S. and is associated with serious cardiometabolic complications and shortened life span. Several lines of evidence suggest that HFCS in the diet affects triglyceride storage, lipid kinetics, and insulin sensitivity in the liver, and epidemiologic studies have correlated consumption of HFCS with incidence and severity of NAFLD and insulin resistance. However, most studies conducted in people have involved overfeeding fructose in persons with normal intrahepatic triglyceride (IHTG) content, which does not address the weight gain independent effect of consuming HFCS or the effects of HFCS consumption in a high-risk population. The goal of this proposal was to provide new insights into the in vivo metabolic effects of HFCS in subjects with NAFLD, clarifying the role of HFCS in the increased hepatic triglyceride storage, lipid kinetics, and insulin sensitivity seen in patients with NAFLD. This protocol has been expanded to include a BMI-matched group of subjects without NAFLD with the award of the K23 Mentored Career Development Award by the National Institutes of Health. The success of the K23 application was in large part due to the Longer Life Foundation Developmental Research Award.

 Methods:
So far, three obese persons with NAFLD were randomized to four weeks of a weight maintenance diet high in HFCS (n = 1, 25% of calories from HFCS) or four weeks of a weight maintenance diet low in HFCS (n = 2, <5% calories from HFCS) after two weeks on a run-in diet low in HFCS. One obese person with normal liver fat content completed four weeks of a weight maintenance diet high in HFCS (n = 1, 25% of calories from HFCS) after two weeks on a run-in diet low in HFCS. Magnetic resonance spectroscopy was used to determine liver fat content; stable isotope infusions with compartmental modeling were used to determine hepatic lipid kinetics, de novo lipogenesis and uric acid production; and a hyperinsulinemic euglycemic clamp study was used to determine liver and skeletal muscle insulin sensitivity.

 Results:
The four-week high HFCS diet did not result in an increase in liver fat; however, the two-week low HFCS run-in diet resulted in a 44 ± 5% decrease in IHTG content, which persisted on the high HFCS diet. Total serum cholesterol also decreased on the run-in low HFCS diet (186.8 ± 23 to 146.5 ± 28, p = 0.024). Further subjects are necessary to evaluate between group differences on the four-week intervention diets.

 Discussion:
These early findings suggest that the low HFCS run-in diet has beneficial effects on liver fat and serum lipids. Further subjects are needed in each group to determine the between-group differences. With the expanded protocol, comparisons will be made between obese persons with NAFLD on the high HFCS diet for four weeks and obese persons with NAFLD on the low HFCS diet for four weeks as well as obese persons with NAFLD on the high HFCS diet for four weeks and obese persons with normal liver fat on the high HFCS diet for four weeks.

 Future Directions:
We expect to finish the current proposal with manuscript submission by April 2016. Preliminary data from this will be used to apply for R01 funding to study the effect of HFCS compared with sucrose and a control low-total sugar group to determine if the effects seen in this study are due to the type of sugar consumed or the total amount of sugar consumed in a weight-stable diet in obese persons with NAFLD.