Fatty liver could be caused by E-cigarette smoke.

Researchers found that regular e-cigarette exposure may lead to an accumulation of fat in the liver. Their conclusion was based on an animal study on mice. These research findings are presented at ENDO 2018, the Endocrine Society’s 100th annual meeting in Chicago, Illinois.

This study was led by Theodore C. Friedman, M.D., Ph.D., Chairman of the Department of Internal Medicine and Endowed Professor of Cardio-Metabolic Medicine at Charles R. Drew University of Medicine & Science in Los Angeles, California.

In this research study, researchers studied mice without apolipoprotein E gene as these are more prone to developing heart disease and non-alcoholic fatty liver disease. Study randomized these mice into two groups one was exposed to saline aerosol and other to e-cigarette smoke. Both were fed the same diet. Researchers analyzed liver samples from both mice. They then examined gene expression by using RNA sequence analysis and found that mice which were exposed to e-cigarette smoke had changes in 433 genes associated with fatty liver and circadian rhythm dysfunction.

It is noted that non-alcoholic fatty liver disease and liver is associated with nicotine use and circadian rhythm dysfunction.

Adapted from press release by the Endocrine Society.

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.

Understaning Pathogenesis of Pancreatic Cancer Metastasis to Liver

Adapted from press release by Technical University of Munich (TUM)

Pancreatic cancer is an exceptionally aggressive type of cancer. Frequently, metastases already start to grow in other organs, particularly often in the liver, before the original tumor was even detected. Scientists from the Technical University of Munich (TUM) have now discovered a molecular mechanism, which is responsible for the prominent susceptibility of the liver to pancreatic metastases at such an early stage.

While some forms of cancer are increasingly treatable, the prognosis for patients with pancreatic tumors remains poor. One of the reasons is that, compared with other tumors, they spread to other organs as metastases exceptionally early and efficiently. In well over half of the cases, these metastases grow in the liver. A team of scientists headed by biologist Professor Achim Krueger from the Institute of Molecular Immunology and Experimental Oncology at TUM’s Klinikum rechts der Isar, investigated the reasons for this and published the results in the journal Gastroenterology.

In recent years, scientists working in cancer research became increasingly interested in TIMP1, a protein produced naturally in the body. Initially, TIMP1 was of interest because of its protease-inhibiting properties. Proteases are enzymes that play an important role in the human body, for example in the formation of organs, but they can also facilitate transportation of cancer cells from the original tumor to distant organs. In the latter case, they act as biochemical machetes, which clear a path for the tumor cells through the tissue and into the blood or lymphatic system, and allow them to infiltrate distant organs. It was long believed that TIMP1 could therefore serve as a model for anti-cancer medication.

Paradoxically, however, research showed that, for many tumor diseases, increased TIMP1 values are associated with bad prognosis of cancer patients. TIMP1 thus correlates with an increase in the aggressive spread of cancer cells to other organs. In order to find an explanation for this, the group led by Achim Krueger has been investigating the unknown functions of the TIMP1 molecule for several years now.

The scientists now were able to establish that TIMP1 is already produced during the non-malignant preliminary stages of pancreatic cancer and even during chronic pancreatitis. The protein is then transported to the liver via the blood stream, There, its interaction with another molecule, which is located on the hepatic stellate cells, has far-reaching consequences. These cells are usually inactive and are only activated by pathological processes, such as an infection, leading to processes which can counteract the changes.

TIMP1, when transported from the pancreas into the liver, does not display its protease-inhibiting features for which it was originally known, as there are no proteases to be inhibited in the healthy liver. However, Achim Krueger and his team were able to demonstrate for the first time that TIMP1 takes action nonetheless; it binds to a receptor on the stellate cells, which is called CD63. As a result, the stellate cells are activated and a complex process in the liver is initiated, the details of which the researchers explain in their article. “The end of this process is the development of kind of a niche, which provides particularly good conditions for the growth of metastases and shows them the way to the liver,” says Barbara Gruenwald, first author of the study.

“Our study shows that this process is already set in motion long before tumors in the pancreas become malignant,” adds Achim Krueger. “This enables us to explain the exceptionally aggressive rate of this type of tumor.” The results of the study also suggest that the classical notion of a linear development of tumors needs to be reconsidered. This notion implies, briefly, that metastases form solely as a result of the capabilities of malignant tumor cells, which in turn arise only through multiple conversion processes of benign tumors. “As we have shown, however, a path for the aggressive spread of tumors can be opened up in the very early stages of the disease,” states Achim Krueger. Krueger and his team are currently working on ways to prevent the binding of CD63 to TIMP1 before tumor cells can exploit this niche. “The challenge in this endeavor lies in the fact that TIMP1 also performs important functions,” says Krueger. “Simply suppressing TIMP1 would cause serious side effects, as cancer cells might spread even more aggressively to other parts of the body in absence of the protease inhibitor. We are therefore striving to find a substance which is able to maintain the inhibitory effect of TIMP1 but prevents its binding to CD63.”

Publication: Pancreatic Premalignant Lesions Secrete Tissue Inhibitor of Metalloproteinases-1, Which Activates Hepatic Stellate Cells Via CD63 Signaling to Create a Premetastatic Niche in the Liver. DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.043