Low IGF-1 Associated with Fatty Liver
An important aspect in terms of how fatty liver happens.
Study Title:Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2.
Non-alcoholic fatty liver disease is associated with multiple comorbid conditions, including diabetes, obesity, infection, and malnutrition. Mice with hepatocyte-specific disruption of growth hormone (GH) signaling develop fatty liver (FL), although the precise mechanism underlying this finding remains unknown. Because GH signals through JAK2, we developed mice bearing hepatocyte-specific deletion of JAK2 (referred to herein as JAK2L mice). These mice were lean, but displayed markedly elevated levels of GH, liver triglycerides (TGs), and plasma FFAs. Because GH is known to promote lipolysis, we crossed GH-deficient little mice to JAK2L mice, and this rescued the FL phenotype. Expression of the fatty acid transporter CD36 was dramatically increased in livers of JAK2L mice, as was expression of Pparg. Since GH signaling represses PPARγ expression and Cd36 is a known transcriptional target of PPARγ, we treated JAK2L mice with the PPARγ-specific antagonist GW9662. This resulted in reduced expression of liver Cd36 and decreased liver TG content. These results provide a mechanism for the FL observed in mice with liver-specific disruption in GH signaling and suggest that the development of FL depends on both GH-dependent increases in plasma FFA and increased hepatic uptake of FFA, likely mediated by increased expression of CD36.
From press release:
Scientists at the UCSF Cardiovascular Research Institute have discovered how a change in growth hormone activity in mice leads to fatty liver disease, a condition whose human counterpart is of rising concern worldwide.
Disruption of a key protein in the pathway that responds to growth hormone could explain how fatty liver disease develops, the researchers said, but may also offer insights into how our bodies regulate fat in general.
The team’s findings and the first reports of a mouse model to study the pathway will appear in the April issue of the Journal of Clinical Investigation and online March 1.
Until recently, the growth of fat deposits in the liver that characterizes fatty-liver disease was mainly considered a result of alcoholism. Over the last decade, though, scientists have been baffled by the rising incidence of the non-alcoholic version of the disease, which now affects as many as one in four people worldwide, according to UCSF cardiologist Ethan Weiss, MD, senior author of the paper.
Known risk factors for the condition include obesity, diabetes and malnutrition, among many others, but its precise mechanism had eluded researchers.
“Fatty liver disease is an increasingly prevalent condition that is poorly understood,” Weiss said. “We knew that growth hormone had been linked to fatty liver, but previous reports showed that it both causes and cures the condition. We set out to figure out why that happens.”
The team focused on a protein in the liver known as JAK2. While better known as being linked to cancers such as blood cancers, this protein is also a key player in an important chemical pathway in the liver.
Normally, the pituitary gland secretes growth hormone, which communicates with JAK2 and sets off a series of steps to produce insulin-like growth factor 1 (IGF-1), an important mediator of growth and other effects. It was common knowledge that disrupting this pathway would halt IGF-1 production, but in their analysis, Weiss and his team found that disrupting the pathway also caused fatty liver disease.
The team engineered a mouse model in which the gene producing JAK2 had been removed solely in the liver, disrupting the pathway that produces the insulin-like growth factor. As expected, the levels of growth factor in these mice were low or nonexistent and the mice developed early and severe fatty-liver disease. Further analysis showed that another protein, called CD36, was working in the liver to draw in the fat in the JAK2-deficient mice.
The amount of growth hormone secreted by the pituitary gland also was dramatically elevated. The team realized that low IGF-1 levels were sending the pituitary gland into overdrive, secreting more growth hormone in order to jumpstart the growth factor’s production. But without JAK2, the signaling pathway was broken and IGF-1 production was at a standstill.
That explained the low growth factor levels, but not the fatty livers. The team then took advantage of a second set of mice with no capability of producing growth hormone, which is known to activate energy from fat stores. When crossing the JAK2-deficient mice with the growth hormone-deficient “little” mice, the researchers noticed a huge difference in the offspring.
“We saw a complete disappearance of the fatty liver in these offspring,” he said. “It was just gone.”
The team concluded that the growth hormone signaling pathway is not only essential in producing IGF-1 and mobilizing fat, but in regulating how fat is taken up by the liver.
This newfound understanding has huge implications for understanding and treating fatty liver disease in humans, Weiss said, such as the possibility of developing a therapeutic drug that works within this pathway.
Brandon C. Sos, Charles Harris, Sarah M. Nordstrom, Jennifer L. Tran, Mercedesz Balázs, Patrick Caplazi, Maria Febbraio, Milana A.B. Applegate, Kay-Uwe Wagner and Ethan J. Weiss. Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2. Journal of Clinical Investigation 2011 March
Related Entries: Protect and Energize Your Immune System
GMOs, Roundup, and Sunscreen Linked with Diminished Brain Resiliency
Signs of Concussions and Mild Traumatic Brain Injury
Sleep – Molecular Clean Up Time for the Brain
Artificial Sweeteners Provoke High Risk for Diabetes
Hypothyroidism, Brain Stress, and Season Changes
Alcohol, Adolescents, and Young Adults – A Neurological Disaster Waiting to Happen
GABA: Managing Brain Stimulation, Anxiety, and Other Consequences
Brain Fatigue: Fundamental Solutions
Brain Fatigue 101
Astonishing Benefits of Cranberries
Summer Heat Stress – More Than Just Dehydration
Chronic Active Epstein Barr Virus: Additional Tools for the Battle
Pine Nut Oil Reduces Inflammation, Clotting Risk, and Fatty Liver Congestion
New Findings with Epstein Barr Virus: The Sleeping Giant
Type 1 Diabetes: Risk Factor Alert
Disrupted Gut Clocks Linked with IBS, GERD, Obesity, and Other GI Concerns
Body Clocks and Weight Management – It’s All About Timing
Saturated Fat Myth – Debunked Again
Powerful Nutrition for Common Chemical Exposures
Endocrine Disruptor Compounds and Natural Solutions
Endocrine Disruptor Compounds and Your Hormones
Low Blood Pressure Linked with Brain Atrophy
Vitamin K, Leptin, AGEs, and Arthritis
Advanced Solutions for Osteoarthritis
Osteoarthritis: Good Oils versus Bad Oils and Inflammation
High Levels of Omega 6 Fatty Acids Found in Bones of Osteoarthritis Patients Worsens Joint Breakdown
Lipoic Acid Protects the Heart and Immune System from Acute Emotional Stress
Whiplash, Thyroid, and Adrenals
Brain Inflammation Now Documented in Chronic Fatigue Syndrome
Brain Protective Effects of Proathocyanidins
Nutrient Highlight: Discover the Best Form of Folate
Lutein and Zeaxanthin Offset Gene Weaknesses that Cause Macular Degeneration
Lycopene Builds Its Anti-Prostate Cancer Case
Carotenes Improve the Quality of Semen
Vitamin B12 as Methylcobalamin Repairs Nerves & Lowers Pain
Folic Acid Activates Neural Stem Cells for Brain Rejuvenation
Chromium Improves Insulin Function & Reduces Binge Eating
How Fiber and Niacin Protect Against Colon Inflammation and Cancer
Berries Have Anti-Aging Impact on Immune System
Strawberries Reduce Cardiovascular Risk
Friendly Flora Improves Fatty Liver Disease
Flavonoid Intake Improves Cardio Health in At-Risk Men
Polyphenols and Essential Fatty Acids Reduce Cardio Risk in Overweight People
Vitamin C Reduces the Risk for Hemorrhagic Stroke
Testosterone Therapy Increases Heart Attack Risk
Magnesium Intake Linked to Lower Cardiovascular Inflammation
Q10 Boosts Energy, Nerves, Muscles & Metabolism
Coenzyme Q10 Remarkably Improves Circulation
Tyrosine Helps Maintain Mental Ability Under Stress
Green Tea Extract Lowers Blood Pressure, Cholesterol, Blood Sugar & Inflammation
Poor Flexibility is a Sign of Stiff Arteries
A Sluggish Lymph System Causes Snoring & Sleep Apnea
DHA is Vital to Cardiovascular Wellness
Magnesium Supplements Lower Blood Pressure, Prevent Calcification
Magnesium for the Prevention of Heart Disease
Pomegranate Protects HDL Cholesterol from Damage
Pomegranate Blocks Flu Replication
Tocotrienols: Twenty Years of Dazzling Cardiovascular and Cancer Research
Is Resveratrol the Fountain of Youth?
Grape Seed Extract Lowers Blood Pressure
Scientists Tout Resveratrol as a Primary Nutrient for Cardio Health
Leptin, Thyroid, and Weight Loss
Excess Appetite Causes Abdominal Fat
Low Energy? Detect Thyroid Related Fatigue
Curcumin Boosts AMPK Activation, Prevents Fatty Liver
Quercetin Activates Mitochondrial Biogenesis
Quercetin Guards Against Inflammation-Induced Bone Loss
Head Injuries Double or Triple the Risk of Early Death
Fatty Fish Consumption Lowers the Risk of Type 2 Diabetes by 33%
Flavonoids Continue to Show Potent Diabetes Prevention
Vitamin K2 Decreases Bone Loss in Postmenopausal Women
Cissus Quadrangularis Enhances Fracture Healing
Cissus Quadrangularis Reduces Exercise-Related Joint Pain
Nobiletin and Tangeretin Help Protect Against Bone Loss
Nobiletin and Tangeretin Inhibit Respiratory Virus
Oregano Oil Inhibits Biofilm Formation
Bromelain Helps Chronic Sinus Inflammation
Curcumin Demonstrates Potent Anti-Flu Properties
Quercetin Protects Brain and Body from Low Oxygen Stress
Ubiquinol Q10 Protects Against Magnified Tissue Injury
Ubiquinol Q10 Protects Eyes of Diabetic Patients
Limonene Promotes Healing of Digestive Lining
Magnesium Intake Reduces Mortality
Fiber is Vital for Cardio Health
Friendly Flora Boosts Weight Loss in Obese Women
Tocotrienols Help Correct Fatty Liver in Humans
Vitamin E Boosts Quality of Life for Alzheimer’s Patients
Astaxanthin Demonstrates Brain Protection & Rejuvenation
Top 10 Health Stories of 2013
Resveratrol’s Amazing Anti-Aging Effect on Circulation
Grape Seed Extract Normalizes Blood Pressure in Mild Hypertension Patients
Don’t Let Bacterial Infections Set Up Shop
Viral Replication Fueled by Sugar
Anti-Vitamin Propaganda Hits a Fever Pitch
Antacid Medications Cause Vitamin B12 Deficiency, Speed Aging
Men Should Take Folic Acid Prior to Conception to Prevent Birth Defects
Exercise Potently Reduces the Risk for Diseases of Aging
Fisetin Demonstrates Potent Bone Protection Properties
Most Popular News:
Connect with Wellness Resources: