New plant based compounds show promise for hepatitis B

Researchers have found that certain plant-derived products may help prevent and treat hepatitis B virus (HBV) infection. Proanthocyanidin (PAC) and its analogs, oolonghomobisflavanes, act by inhibiting viral entry into host cells.

Hepatis B life cycle
The life cycle of Hepatitis B Virus. Credit Dr. Graham Colm Wikipedia

The investigators noted that PAC was effective even against treatment-resistant HBV strains, and it augmented the ability of the antiviral drug tenofovir to interrupt HBV spread in human cells.

“PAC represents a specific inhibitor against HBV that is a less toxic plant-derived agent used as a dietary supplement,” said Dr. Koichi Watashi, co-author of the Hepatology study.

Senko Tsukuda, Koichi Watashi, Taichi Hojima, Masanori Isogawa, Masashi Iwamoto, Katsumi Omagari, Ryosuke Suzuki, Hideki Aizaki, Soichi Kojima, Masaya Sugiyama, Akiko Saito, Yasuhito Tanaka, Masashi Mizokami, Camille Sureau and Takaji Wakita. “A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins.” Hepatology 2017.
DOI: 10.1002/hep.28952
Adapted from press release by Wiley Publications.

Researcher discover role of protein CPEB4 in development of fatty liver

The scientists at IRB Barcelona discovered the role of a protein CPEB4 in the pathogenesis of nonalcoholic steatohepatitis (fatty liver). This condition generally leads to chronic inflammation, which can trigger fibrosis, cirrhosis and ultimately liver cancer. This study paves the way to examine therapeutic strategies to fight and prevent this disease. The results of the study are published in journal Nature Cell Biology.

CPEB4 Fatty Liver
Staining of mouse liver sections showing steatosis of the liver (fatty liver), with accumulation of fat, lipid droplets (in red), within cells. Cell nuclei stain blue. Credit: C. Maillo, IRB Barcelona

Non-alcoholic fatty liver is characterized by the accumulation of fat deposits in hepatocytes. The development of this condition is determined by many factors that have not been well described to date. However, obesity and lifestyle, as well as aging, are associated with an increase in the incidence of this disease. Also, a number of large-scale genomics studies have linked variants of the CPEB4 gene with the impairment of fat metabolism.

The scientists depleted CPEB4 expression in mouse livers in order to study the function of this protein. They observed that the mice developed fatty liver as they aged. Furthermore, young CPEB4-depleted mice fed a high-fat diet also developed this condition in a more pronounced manner.

Carlos Maíllo, the first author of the article has described the molecular function of CPEB4. He reveals that this protein is essential to drive the liver stress response. Specifically, under stress, caused by uncontrolled ingestion of fats for example, the endoplasmic reticulum–a cell organelle associated with protein synthesis and folding and lipid metabolism stops its activity in order to re-establish cell equilibrium. This “clean-up” mechanism is orchestrated by CPEB4 and varies in function of the time of day being more active in humans during the day (when the liver has most work) and dropping off at night. Without CPEB4, the endoplasmic reticulum is unable to activate the stress response, thus causing hepatocytes to accumulate the lipids produced by the fatty liver.

Raúl Méndez, ICREA researcher at IRB Barcelona and co-leader of the study, explains that “knowledge of the hepatic function of CPEB4 could be useful as a predictive marker for those people with variants of this protein, thus serving to prevent this condition, for example, through improvements in diet and better choice of eating times. Such knowledge could also contribute to the development of treatments that boost the clean-up process”.

The researchers have managed to reverse fatty liver disease in mice by treatment with a drug called Tudca, which is currently used for other disorders. This drug exerts the same function as the proteins that are activated by CPEB4 and that are responsible for cleaning up the cell, namely chaperones. “In the future it may be possible to design molecules like Tudca that specifically target CPEB4, thus enhancing the liver clean-up process,” proposes Méndez.

“This basic research study does not have a direct and immediate clinical application, but it lays down the foundation for the applied science that follows,” says Mercedes Fernández, co-leader of the study and head of the group at IDIBAPS and the Biomedical Research Networking Center of Hepatic and Digestive Diseases (CIBEREHD).

Fernández warns, “Given the obesity epidemic in the US and worldwide, an increase in those affected by non-alcoholic fatty liver disease is expected in the coming decades and we still do not have a suitable treatment for this condition; A fundamental understanding of this medical problem is therefore essential for development of novel treatment strategies.”

Citation: Maillo, Carlos, Judit Martín, David Sebastián, Maribel Hernández-Alvarez, Mar García-Rocha, Oscar Reina, Antonio Zorzano, Mercedes Fernandez, and Raúl Méndez. “Circadian-and UPR-dependent control of CPEB4 mediates a translational response to counteract hepatic steatosis under ER stress.” Nature Cell Biology (2017).
DOI: 10.1038/ncb3461
Research funding: Worldwide Cancer Research Foundation, Spanish Association Against Cancer, Fundación Botín by Banco Santander through its Santander Universities Global Division, Spanish Ministry of Economy and Competitiveness/ERDF and Government of Catalonia.
Adapted from press release by IRB Barcelona.

New approach to treating non-alcoholic fatty liver disease

Researchers from the University of South Carolina, Duke University, the University of Alabama at Birmingham, and Metabolon Inc. Research Triangle Park has discovered a new pathway in the liver that opens the door to treating non-alcoholic fatty liver disease, a condition that affects up to 25 percent of the population and may lead to cirrhosis and eventually liver cancer or failure, and likely other liver diseases. The study was published in Free Radical Biology & Medicine, one of the leading scientific journals in the field of oxidative stress and medicine.

The team found that a protein (TRPV4), which is a part of the body’s defense system, is able to activate the release of a gas (nitric oxide). This gas then blocks one of the enzymes (CYP2E1) that is a major contributor to non-alcoholic liver disease and its progression. TRPV4 is already known to protect against cardiovascular abnormalities.

Now that this protein’s capacity to block the development of non-alcoholic fatty liver disease has been discovered, the next step is to harness its preventive and treatment abilities. According to the authors, a new generation of TRPV4 agonists can now be tested to improve outcomes related to non-alcoholic fatty liver disease. The agonist is a chemical that will bind to this protein and activate the release of nitric oxide to block the harmful enzyme. Once the appropriate agonist is identified, it can be incorporated into medication for clinical treatment.

“There are currently no clinically proven drugs to treat non-alcoholic fatty liver disease,” says Saurabh Chatterjee, an associate professor of environmental health sciences at the University of South Carolina’s Arnold School of Public Health and the director of the Environmental Health and Disease Laboratory where the research was led. “Our goal is to find novel pathways in the liver that will result in a road to a cure, and this novel internal defense mechanism within the liver offers a very promising route.”

In addition to revealing the benefits of activating TRPV4, the researchers also warn against the consequences of inhibiting the TRPV4 ion channel, an approach that can enhance hepatotoxicity (i.e., liver damage caused by chemicals), which can result from acetaminophen or alcohol over-consumption.

“This means that one has to be careful when aiming to inhibit TRPV4 for therapeutic purposes, such as when treating pain, inflammation or itching, or other conditions, in particular when inhibiting TRPV4 by systemic application of TRPV4-blockers,” says Wolfgang Liedtke, a professor of neurology, anesthesiology and neurobiology at Duke University School of Medicine who first described TRPV4 16 years ago. “An attractive avenue to meet this therapeutic dilemma is to use herbal-derived TRPV4-activating compounds that might be more ‘gentle’ or targeted genetic manipulations of liver cells aiming to facilitate TRPV4-signaling in the liver when treating non-alcoholic fatty liver disease. These methods could also be a suitable approach to balance an eventually-needed systemic inhibition of TRPV4 that one aims for in order to treat pain, inflammation, fibrotic diseases or lung edema, in order to avoid additional damage to the liver.”

This groundbreaking research has the potential to have a significant impact on both individuals and public health. “This type of research, which seeks novel pathways for the treatment of diseases for which there are currently no therapeutic options is vitally important,” notes collaborator and USC Vice President for Research Prakash Nagarkatti. “It opens doors that lead to the breakthroughs patients rely on to improve outcomes, enhance the quality of life and even save lives.”

The non-alcoholic fatty liver disease occurs when there is a buildup of extra fat in the liver (i.e., more that 5-10 percent of the liver’s total weight) coupled with liver inflammation that is not caused by alcohol.

Affecting both children and adults, this disease tends to occur in individuals who are obese or overweight, have type II diabetes, high cholesterol, and triglycerides. However, some people develop non-alcoholic fatty liver disease without any of these risk factors, possibly suggesting genetic risk factors. Healthy liver function is critical because the liver functions as a metabolic and chemical central laboratory in all vertebrate organisms including humans. For example, it processes food and drink into energy and nutrients, produces bile, blood coagulation factors, and other blood proteins while processing and removing many harmful substances from the blood.

Citation: Seth, Ratanesh K., Suvarthi Das, Diptadip Dattaroy, Varun Chandrashekaran, Firas Alhasson, Gregory Michelotti, Mitzi Nagarkatti, Prakash Nagarkatti, Anna Mae Diehl, Darwin P. Bell, Wolfgang Liedtke & Saurabh Chatterjee. “TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity.” Free Radical Biology and Medicine 2016.
Research funding: National Institutes of Health Pathway to Independence Award, US Department of Defense, Harrington Discovery Institute Scholar-Innovator Award, VA Merit Award.
Adapted from press release by the University of South Carolina.

Research finds bi-directional association between fatty liver disease and heart disease

Researchers have shown that a bi-directional relationship exists between fatty liver disease and cardiovascular disease. Fatty liver disease can lead to increased cardiovascular disease risk and vice versa. The findings, which appear in the Journal of Hepatology, are important in understanding the link between fatty liver disease and cardiovascular disease, which continues to be one of the major causes of morbidity and mortality worldwide.

Due to the increased prevalence of obesity, non-alcoholic fatty liver disease has become the most common liver disease in the U.S., affecting 20-30 percent of the adult population. Obesity is also an independent risk factor for cardiovascular disease — so both diseases exist in many patients. Previous studies have shown that there is a link between fatty liver and cardiovascular disease however it is not fully understood if fatty liver disease precedes or develops after cardiovascular disease.

Using data from participants in the Framingham Heart Study, researchers saw that individuals with fatty liver disease developed cardiovascular diseases such as high blood pressure and type 2 diabetes within six years. In a parallel analysis, individuals with high blood pressure, type 2 diabetes, or high triglycerides had a higher likelihood of developing fatty liver disease.

In our study, we observed a bi-directional association between fatty liver and cardiovascular disease,” explained corresponding author Michelle Long, MD, assistant professor of medicine at Boston University School of Medicine (BUSM), who also is a gastroenterologist at Boston Medical Center (BMC). “We observed that fatty liver was an important factor in the development of high blood pressure and diabetes and the opposite also stands true – various cardiovascular diseases were associated with the development of fatty liver disease over six years,” she added.

Long believes this study highlights the need to develop both preventative and treatment strategies for fatty liver disease in order to improve the cardiovascular health of all people.

Citation: Ma, Jiantao, Shih-Jen Hwang, Alison Pedley, Joseph M. Massaro, Udo Hoffmann, Raymond T. Chung, Emelia J. Benjamin, Daniel Levy, Caroline S. Fox, and Michelle T. Long. “Bidirectional relationship between fatty liver and cardiovascular disease risk factors.” Journal of Hepatology (2016).
Funding: NIH/National Heart, Lung and Blood Institute, Boston University School of Medicine.

Adapted from press release by Boston University School of Medicine.

Researchers developed method of determining liver disease with blood tests

A new non-invasive method of predicting the risk of developing a severe form of liver disease could ensure patients receive early and potentially life-saving medical intervention before irreversible damage is done.

Using information collected in a liver biopsy study, researchers at Cardiff University have developed a method of determining the onset of non-alcoholic steatohepatitis (NASH) through the analysis of lipids, metabolites and clinical markers in blood. The study is published in Clinical Gastroenterology and Hepatology.

NASH is the most extreme form of non-alcoholic fatty liver disease (NAFLD) – a range of conditions caused by a build-up of fat in the liver. With NASH, inflammation of the liver damages the cells, potentially causing scarring and cirrhosis.

Currently, the diagnosis of NASH can only be done with a liver biopsy – an invasive and costly procedure. The new research could lead to a simple blood test that could catch the onset of NASH before inflammation damages the liver.

Dr You Zhou from Cardiff University’s Systems Immunity Research Institute said: “Many people with non-alcoholic steatohepatitis do not have symptoms and are not aware they are developing a serious liver problem. As such, diagnosis often comes after irreversible damage is done. Our quicker and less invasive method of diagnosis could mean that more people with non-alcoholic fatty liver disease could be easily tested to determine whether they are progressing to non-alcoholic steatohepatitis, the more severe form of the disease.”

A healthy liver should contain little or no fat. It’s estimated that around 20% of people in the UK have early stages of NAFLD where there are small amounts of fat in their liver. NASH is estimated to affect up to 5% of the UK population and is now considered to be one of the main causes of cirrhosis – a condition where irregular bumps replace the smooth liver tissue, making it harder and decreasing the amount of healthy cells to support normal functions. This can lead to complete liver failure.
Common risk factors for both NAFLD and NASH are obesity, lack of physical exercise and insulin resistance. But if detected and managed at an early stage, it’s possible to stop both NAFLD and NASH from getting worse.

The new method of NASH diagnosis will undergo further investigation with a view to developing a simple blood test that can be used by clinicians to provide effective medical care for patients at high risk of the disease.
Publication: Noninvasive Detection of Nonalcoholic Steatohepatitis Using Clinical Markers and Circulating Levels of Lipids and Metabolites
Simple blood test could vastly improve detection rates of severe liver disease