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Wednesday, Feb. 8, 2023

Heart Disease and Fatty Liver Diseases


Providing the link between America’s common diseases

Since the early 1900s, the United States has seen a steady rise in the number of heart disease-related deaths, reaching a peak in the 1970s. The introduction of drugs to treat high blood pressure (ACE inhibitors) or high cholesterol (statins), as well as education to the public about the dangers of smoking, poor diet and lack of exercise, led to a drop in the number of deaths due to heart disease. Despite these encouraging trends, the United States has seen a rise in heart disease-related deaths during the last decade. Importantly, heart disease remains the number one cause of death not only in the United States but in the world.

Why is this happening? Modern medicine has made enormous strides in recent decades in detecting and combatting heart disease, which is caused when fatty plaques build up in the blood vessels causing them to narrow and block blood flow. For example, routine blood work and CT imaging can detect and find heart disease risk factors; bypass grafting can fix blockages in the blood vessels; and there is a wide range of available medicine to lower high blood pressure and high cholesterol. However, many cases of heart disease are complicated by additional problems like obesity or diabetes, called metabolic comorbidities, that are increasing in numbers with no signs of slowing down.

While just over 10% of American adults were obese in 1975, about 41% of adults are obese in the United States today. Pertaining to type 2 diabetes, there are nearly 50% more cases in the American population than there were 20 years ago. To further complicate things, people with obesity or diabetes are far more likely to have nonalcoholic fatty liver disease (NAFLD), the buildup of liver fat in those who drink little or no alcohol. Six out of 10 diabetics and nine out of 10 people with obesity have NAFLD.

Nonalcoholic fatty liver disease begins as fatty liver, which is when extra fat accumulates in the liver cells. This can cause a response by the immune system called nonalcoholic steatohepatitis (NASH). NASH may advance to scarring of the liver (fibrosis) that can cause the liver to stop working well, which is called cirrhosis. In the most advanced stages of NAFLD, the liver may develop cancer, and this stage often requires a liver transplant. Despite significant research and drug development efforts, no pharmacological treatment is available for NAFLD. Even though NAFLD increases the risk of liver-related death, the majority of people with NAFLD actually die from heart disease. This means that these two diseases are closely linked, highlighting the importance of studying NAFLD and heart disease together.

Even though the scientific community acknowledges the relationship between heart disease and NAFLD, there are still many aspects that we don’t have answers to for a variety of reasons:

• We don’t yet have a good model for looking at both diseases simultaneously.

• Most people with NAFD and heart disease have no symptoms, and routine blood tests provide limited information.

• Clinical trials evaluating drugs for safety and efficacy focus either on NAFLD or heart disease, but not both.

This is important because we don’t know if drugs currently being tested for the treatment of NAFLD will have good or bad side effects on heart disease.

With this in mind, the Rom Laboratory for Cardiometabolic and Liver Research at LSU Health Shreveport (Rom Lab) studies new ways to look at both heart disease and NAFLD, hopefully leading to drugs that treat both at the same time. The Rom Lab is supported by and collaborates with the Center for Cardiovascular Diseases and Sciences (CCDS) at LSU Health Shreveport, a research Center of Excellence.

The Rom Laboratory has been a part of the CCDS since 2021 when Dr. Oren Rom joined the LSUHS faculty. Since joining, the lab has received funding from the CCDS to help support a part of our research and provide professional development for trainees. Supported by the National Institute of Health and the American Heart Association, the Rom Lab is particularly interested in identifying new metabolic pathways commonly disrupted in NAFLD and heart disease. We hope that by correcting these defective pathways, we can treat these two major diseases at the same time. To do so, we use a multidisciplinary approach in which we study patients with NAFLD and heart disease, genetically engineer new animal models, use dietary manipulation to closely mimic human diseases, and apply a variety of unbiased research tools in metabolism, biochemistry, molecular biology and genomics.

Our integrative approach identified a unique pattern of imbalances in specific amino acids, the building blocks used by the body to make protein, both in NAFLD and heart disease, in human and animal models. Alongside other members of the LSU Health Shreveport CCDS, the Rom Lab frequently combines interests from multiple labs to form important collaborations, which helps advance our current knowledge of heart disease.

Specifically, the Rom Lab found that the simplest amino acid, glycine, is lower in both NAFLD and heart disease. Although glycine has the simplest molecular structure, it plays very important roles as the building block of essential molecules in the body, such as glutathione – one of the most important antioxidants that prevents oxidative damage. We discovered that special proteins, called enzymes, responsible for making glycine in the liver (glycine biosynthesis enzymes) are changed by both NAFLD and heart disease. When these enzymes don’t work properly, both NAFLD and heart disease get worse. The Rom Lab thinks this is caused by low glycine and glutathione antioxidant available to combat oxidative damage in NAFLD and heart disease.

In addition, the lab found that when less glycine is being made, damaging byproducts (oxalate, toxic bile acids and ceramides) are formed and increase inflammation in both diseases. Building on these discoveries, the lab found glycine-based compounds and ways to restore the function of glycine biosynthesis enzymes that lowered NAFLD and heart disease in small and large animal models and led to preclinical and clinical evaluation. We hope our findings will be used to treat patients with both NAFLD and heart disease.

Dr. Rom is supported by grants from the National Institute of Health (R00 HL 150233 and R01 DK134011).

Dr. Finney is supported by a Malcolm Feist postdoctoral fellowship from the Center for Cardiovascular Diseases and Sciences, LSU Health Shreveport, and the American Heart Association (23POST1026505).

Alexandra C. Finney, Ph.D., Pathology and Translational Pathobiology Fellow at LSU Health Shreveport. Oren Rom, Ph.D. RD, assistant professor of pathology and translational pathobiology, LSU Health Shreveport.


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