De Novo Lipogenesis, Lipid and Carbohydrate Metabolism in Non-alcoholic Fatty Liver Disease
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Gastrointestinal, Diabetes |
| Therapuetic Areas: | Endocrinology, Gastroenterology |
| Healthy: | No |
| Age Range: | 18 - 60 |
| Updated: | 8/22/2018 |
| Start Date: | September 2007 |
| End Date: | June 2020 |
The worldwide epidemic of obesity is paralleled with increased cases of non-alcoholic liver
disease (liver fat accumulation) and diabetes. Fat belongs in the adipose tissue, and if
excess fat accumulates in the liver or muscle, these tissues cannot use sugar efficiently. It
has been discovered that when large quantities of fructose (a sugar present in soft drinks)
are consumed, the conversion of carbohydrate (CHO) to fat in the liver increases.
We hypothesize that: 1) subjects with fatty liver have a higher CHO uptake and conversion to
fat in their liver when compared to matched control subjects with normal liver fat content;
and that: 2) when subjects with fatty liver are fed a diet limiting fructose and simple
sugars will decrease their liver CHO fat content. This reduction in liver fat will normalize
the way the liver responds to sugar and insulin, reversing the pre-diabetic state.
The measurement of these parameters will be done using state-of-the-art techniques such as
safe non-radioactive isotope tracers and non-invasive magnetic resonance spectroscopy.
For more information, please call 415-206-5532 for a phone screening
disease (liver fat accumulation) and diabetes. Fat belongs in the adipose tissue, and if
excess fat accumulates in the liver or muscle, these tissues cannot use sugar efficiently. It
has been discovered that when large quantities of fructose (a sugar present in soft drinks)
are consumed, the conversion of carbohydrate (CHO) to fat in the liver increases.
We hypothesize that: 1) subjects with fatty liver have a higher CHO uptake and conversion to
fat in their liver when compared to matched control subjects with normal liver fat content;
and that: 2) when subjects with fatty liver are fed a diet limiting fructose and simple
sugars will decrease their liver CHO fat content. This reduction in liver fat will normalize
the way the liver responds to sugar and insulin, reversing the pre-diabetic state.
The measurement of these parameters will be done using state-of-the-art techniques such as
safe non-radioactive isotope tracers and non-invasive magnetic resonance spectroscopy.
For more information, please call 415-206-5532 for a phone screening
Non-alcoholic fatty liver disease (NAFLD) is the most common liver ailment in developed
countries. Fatty liver - steatosis - affects up to one third of the population. Its
prevalence is rising and seems to parallel the global increase in obesity and type-2
diabetes. The etiology of NAFLD in humans is not well understood. We propose that the hepatic
conversion of carbohydrates (CHO) to lipids (de novo lipogenesis, DNL) is a key factor in the
accumulation of excess liver fat and the accompanying dyslipidemia and hepatic insulin
resistance; and that suppressing DNL by diet will reduce liver fat and improve both lipid and
carbohydrate metabolism in patients with steatosis. These hypotheses are based on studies in
which we and others have established that fractional hepatic DNL can vary dramatically
depending on the diet and/or health status of a subject; and, in particular, that dietary
fructose is a potent lipogenic stimulus. In this proposal we will perform CRC-based studies
to compare the rates of DNL and very low density lipoprotein (VLDL) kinetics in steatotic and
matched non-steatotic controls and evaluate their relationship to lipid profiles and hepatic
and whole-body insulin resistance and overall carbohydrate metabolism (Aim1). The steatotic
individuals whose habitual intake of fructose and other simple sugars exceeds 15% of total
energy intake will then be randomized to consume one of two low-fat diets that differ only in
CHO type to determine whether diet-induced changes in DNL affect liver fat flux and content
and hepatic, whole-body insulin sensitivity, and overall carbohydrate metabolism (Aim 2). We
hypothesize that a diet that is rich in complex CHO will achieve greater decreases in DNL and
liver fat than one that contains typical amounts of simple CHO, including fructose. This
dietary intervention study includes a 6-week 25% energy restriction outpatient phase to
promote moderate weight loss and improve insulin sensitivity, followed by a two weeks weight
maintenance with the last 4 days as an inpatient stay during which all of the studies
performed at baseline (Aim 1) will be repeated. State-of-the-art stable isotope techniques
will be used to assess hepatic DNL, apoB100 turnover, VLDL-triglyceride (TG) fluxes, and
lipolysis under fasting and fed conditions. Hepatic and extra-hepatic insulin sensitivity
will be measured using hyperinsulinemic-euglycemic clamps and stable isotope studies of
endogenous glucose production and glycogen flux. Liver and muscle fat will be measured by
proton magnetic resonance spectroscopy (MRS), visceral fat by magnetic resonance imaging
(MRI), and whole-body composition by dual-energy X-ray absorptiometry (DEXA). These studies
will allow us to evaluate the importance of DNL as a mechanism modulating liver fat content
and flux, and the significance of CHO quality in dietary guidance for steatotic patients.
countries. Fatty liver - steatosis - affects up to one third of the population. Its
prevalence is rising and seems to parallel the global increase in obesity and type-2
diabetes. The etiology of NAFLD in humans is not well understood. We propose that the hepatic
conversion of carbohydrates (CHO) to lipids (de novo lipogenesis, DNL) is a key factor in the
accumulation of excess liver fat and the accompanying dyslipidemia and hepatic insulin
resistance; and that suppressing DNL by diet will reduce liver fat and improve both lipid and
carbohydrate metabolism in patients with steatosis. These hypotheses are based on studies in
which we and others have established that fractional hepatic DNL can vary dramatically
depending on the diet and/or health status of a subject; and, in particular, that dietary
fructose is a potent lipogenic stimulus. In this proposal we will perform CRC-based studies
to compare the rates of DNL and very low density lipoprotein (VLDL) kinetics in steatotic and
matched non-steatotic controls and evaluate their relationship to lipid profiles and hepatic
and whole-body insulin resistance and overall carbohydrate metabolism (Aim1). The steatotic
individuals whose habitual intake of fructose and other simple sugars exceeds 15% of total
energy intake will then be randomized to consume one of two low-fat diets that differ only in
CHO type to determine whether diet-induced changes in DNL affect liver fat flux and content
and hepatic, whole-body insulin sensitivity, and overall carbohydrate metabolism (Aim 2). We
hypothesize that a diet that is rich in complex CHO will achieve greater decreases in DNL and
liver fat than one that contains typical amounts of simple CHO, including fructose. This
dietary intervention study includes a 6-week 25% energy restriction outpatient phase to
promote moderate weight loss and improve insulin sensitivity, followed by a two weeks weight
maintenance with the last 4 days as an inpatient stay during which all of the studies
performed at baseline (Aim 1) will be repeated. State-of-the-art stable isotope techniques
will be used to assess hepatic DNL, apoB100 turnover, VLDL-triglyceride (TG) fluxes, and
lipolysis under fasting and fed conditions. Hepatic and extra-hepatic insulin sensitivity
will be measured using hyperinsulinemic-euglycemic clamps and stable isotope studies of
endogenous glucose production and glycogen flux. Liver and muscle fat will be measured by
proton magnetic resonance spectroscopy (MRS), visceral fat by magnetic resonance imaging
(MRI), and whole-body composition by dual-energy X-ray absorptiometry (DEXA). These studies
will allow us to evaluate the importance of DNL as a mechanism modulating liver fat content
and flux, and the significance of CHO quality in dietary guidance for steatotic patients.
Inclusion Criteria:
- In the steatotic subjects, steatosis will be diagnosed by MRS or liver biopsy in which
>33% of the hepatocytes will contain fat. Non-steatotic controls will not have
biopsies since they are not medically warranted; thus, to ensure they do not have
steatosis they will undergo MRS during screening and have a total lipid: unsuppressed
water < 0.05.
Exclusion Criteria:
- Habitual consumption of alcohol > 20 g/day for men and 10 g/day for women
- Confirmed HIV-1 infection, Hgb <13 g/dL for males and <12 g/dL for females
- Abnormal hepatitis B or C serology
- Diabetes or current use of any antidiabetic or hypolipidemic agents
- Presence of metal-containing substances in the body (e.g. a fragment in the eye,
aneurysm clips, ear implants, spinal nerve stimulators or a pacemaker)
- Weight over 350 pounds or severe claustrophobia, which would preclude the MR studies
- Any condition that would preclude adherence to the protocol or the ability to provide
informed consent
- Change in body weight >5% within the preceding 6 months (by self-report)
- Known intolerance, allergy or hypersensitivity to fructose
- Pregnancy or lactation (for women); OR
- Any other condition that, in the opinion of the investigators, would put the subject
at risk.
We found this trial at
1
site
Click here to add this to my saved trials
