TAG: "Liver disease"

Breaking bad mitochondria


Mechanism helps explain persistence of hepatitis C virus.

Researchers at the UC San Diego School of Medicine have identified a mechanism that explains why people with the hepatitis C virus get liver disease and why the virus is able to persist in the body for so long.

The hard-to-kill pathogen, which infects an estimated 200 million people worldwide, attacks the liver cells’ energy centers – the mitochondria – dismantling the cell’s innate ability to fight infection. It does this by altering cells mitochondrial dynamics.

The study, published in today’s (April 15) issue of the Proceedings of the National Academy of Sciences, suggests that mitochondrial operations could be a therapeutic target against hepatitis C, the leading cause of liver transplants and a major cause of liver cancer in the U.S.

“Our study tells us the story of how the hepatitis C virus causes liver disease,” said Aleem Siddiqui, Ph.D., professor of medicine and senior author. “The virus damages mitochondria in liver cells. Cells recognize the damage and respond to it by recruiting proteins that tell the mitochondria to eliminate the damaged area, but the repair process ends up helping the virus.”

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Scientists transform skin cells into functioning liver cells


Study highlights novel reprogramming method, offers new hope for treating liver failure.

Sheng Ding

The power of regenerative medicine now allows scientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and even neurons. However, a method to generate cells that are fully mature — a crucial prerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the Gladstone Institutes and UC San Francisco have made an important breakthrough: they have discovered a way to transform skin cells into mature, fully functioning liver cells that flourish on their own, even after being transplanted into laboratory animals modified to mimic liver failure.

In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cell-derived liver cells to survive once being transplanted into existing liver tissue. But the Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the journal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding, Ph.D., and UCSF Associate Professor Holger Willenbring, M.D., Ph.D., reveal a new cellular reprogramming method that transforms human skin cells into liver cells that are virtually indistinguishable from the cells that make up native liver tissue.

These results offer new hope for the millions of people suffering from, or at risk of developing, liver failure — an increasingly common condition that results in progressive and irreversible loss of liver function. At present, the only option is a costly liver transplant. So, scientists have long looked to stem cell technology as a potential alternative. But thus far they have come up largely empty-handed.

“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order to then grow liver cells,” explained Ding, one of the paper’s senior authors, who is also a professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However, generating these so-called induced pluripotent stem cells, or iPS cells, and then transforming them into liver cells wasn’t always resulting in complete transformation. So we thought that, rather than taking these skin cells all the way back to a pluripotent, stem cell-like state, perhaps we could take them to an intermediate phase.”

This research, which was performed jointly at the Roddenberry Center for Stem Cell Research at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, involved using a “cocktail” of reprogramming genes and chemical compounds to transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells that eventually mature into many of the body’s major organs—including the liver.

“Instead of taking the skin cells back to the beginning, we took them only part way, creating endoderm-like cells,” added Gladstone and CIRM postdoctoral scholar Saiyong Zhu, Ph.D., one of the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that could more readily be coaxed into becoming liver cells.”

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Nutrition influences metabolism through circadian rhythms


Reprogramming of liver “clock” may contribute to metabolic disorders, UC Irvine study finds.

Paolo Sassone-Corsi, UC Irvine

Paolo Sassone-Corsi, UC Irvine

A high-fat diet affects the molecular mechanism controlling the internal body clock that regulates metabolic functions in the liver, UC Irvine scientists have found. Disruption of these circadian rhythms may contribute to metabolic distress ailments, such as diabetes, obesity and high blood pressure.

There’s good news, though. The researchers also discovered that returning to a balanced, low-fat diet normalized the rhythms. This study reveals that the circadian clock is able to reprogram itself depending on a diet’s nutritional content – which could lead to the identification of novel pharmacological targets for controlled diets.

UC Irvine’s Paolo Sassone-Corsi, the Donald Bren Professor of Biological Chemistry and one of the world’s leading researchers on the genetics of circadian rhythms, led the study, which appears in Cell.

Circadian rhythms of 24 hours govern fundamental physiological functions in virtually all organisms. The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day. Changes to these rhythms can profoundly influence human health. Up to 15 percent of people’s genes are regulated by the day-night pattern of circadian rhythms, including those involved with metabolic pathways in the liver.

A high-fat diet reprograms the liver clock through two main mechanisms. One blocks normal cycles by impeding the clock regulator genes called CLOCK:BMAL1. The other initiates a new program of oscillations by activating genes that normally do not oscillate, principally through a factor called PPAR-gamma. Previously implicated in inflammatory responses and the formation of fatty tissue, this factor oscillates with a high-fat diet.

It’s noteworthy, Sassone-Corsi said, that this reprogramming takes place independent of the state of obesity; rather, it’s solely dependent upon caloric intake – showing the remarkable adaptability of the circadian clock.

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Scientists halt deadly organ tissue scarring in its tracks


UCSF-led study uses drug to target fibrosis of lungs, liver and kidney.

Dean Sheppard, UC San Francisco

Dean Sheppard, UC San Francisco

UC San Francisco scientists report that they were able to arrest, and even reverse, tissue scarring of the liver, kidneys and lungs in mice.

The scarring, also known as fibrosis, is a major factor in nearly half of all deaths in developed countries.

“Scarring is a critical component of organ dysfunction in most chronic diseases – kidney failure, liver failure, lung failure, heart failure,” said Dean Sheppard, M.D., UCSF professor of medicine and senior author of the new study. “But there’s no effective therapy for tissue scarring that’s approved by the FDA [Food and Drug Administration]. Although scarring contributes to the progression of all these diseases, we currently have no way to treat it.”

The scientists accomplished the work by targeting a family of proteins on the surface of certain cells.

In the study, first author Neil C. Henderson, M.D., Ph.D., a former postdoctoral associate in Sheppard’s laboratory and now at the University of Edinburgh, and an international team of scientists first devised a genetic technique to selectively knock out a five-member family of receptors known as alpha V integrins (“INT-uh-grins”) in the collagen-producing fibroblast cells of mice. These cells drive the excessive scarring seen in fibrosis.

The genetic deletion had a strong protective effect: Methods that reliably induce liver scarring in normal mice had little effect on mice lacking alpha V integrins. Knocking out alpha V integrins also protected the mice from fibrosis of the lungs and kidney.

On the other hand, the scientists did not observe any protective effect when they knocked out individual members of the alpha V integrin family, suggesting that fibrosis may be best treated by targeting the family as a whole.

The study was reported online on Nov. 10 Nature Medicine.

Based on these findings, members of the team based at St. Louis University in Missouri designed a drug that specifically blocks the action of all five alpha V integrins, and the compound prevented fibrosis as effectively as the genetic deletion of these integrins. Moreover, the drug, known as CWHM 12, was able to prevent the progression of established fibrosis in the liver and lungs, and even to reverse some of the damage caused to those organs by fibrotic disease.

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Researchers ID liver cancer progenitor cells before tumors become visible


UC San Diego findings could help with early detection and therapeutic intervention.

Stained liver biopsy micrograph showing hepatocellular carcinoma cells with Mallory bodies (reds and blacks)

Stained liver biopsy micrograph showing hepatocellular carcinoma cells with Mallory bodies (reds and blacks)

For the first time, researchers at the UC San Diego School of Medicine have isolated and characterized the progenitor cells that eventually give rise to malignant hepatocellular carcinoma (HCC) tumors – the most common form of liver cancer. The researchers found ways to identify and isolate the HCC progenitor cells (HcPC) long before actual tumors were apparent.

Writing in today’s (Oct. 10) issue of the journal Cell, principal investigator Michael Karin, Ph.D., Distinguished Professor of Pharmacology and Pathology, and colleagues report that HcPC take form within dysplastic or abnormal lesions often found in damaged or cirrhotic livers. The liver damage can be due to viral infections like hepatitis or from chronic alcohol abuse.

“It was never established whether dysplastic lesions are just a regenerative (healing) response of the liver triggered by tissue damage or are actually pre-malignant lesions that harbor tumor progenitor cells,” said study co-author Debanjan Dhar, Ph.D., a postdoctoral researcher in Karin’s lab. “Here we show that HcPC are likely derived from dysplastic lesions, can progress to malignant tumors and further demonstrate that the malignant progression of HcPC to full-blown liver cancer depends upon the microenvironment that surrounds them.”

The researchers were able to characterize HcPC based on several biomarkers that distinguish them from normal cells. They also identified cellular signaling pathways activated in HcPC that are critical “to their malignant potential,” said Dhar.

The findings may have profound implications for treating HCC which, while relatively rare in the United States compared to other types of cancer, is difficult to diagnose and treat, with poor prognoses for patients. HCC is usually fatal within three to six months of diagnosis, according to National Institutes of Health data. An estimated 30,000 new cases of liver cancer are diagnosed annually in the U.S., predominantly among men. More than 21,600 Americans die from liver cancer each year, a rate that has been rising slowly for several decades. In other parts of the world, HCC is a major cause of cancer-related deaths.

Most cancers are best detected and treated at the earliest possible stage. HCC is problematic because it develops slowly and frequently displays no symptoms. By the time it is detected, said Dhar, it is usually at an advanced stage with no effective therapy.

“Our findings can be translated into both early detection and therapeutic intervention,” he said. “Better understanding of HcPC cellular networks will provide us with new and effective therapeutic targets.”

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Six months of fish oil reverses liver disease in kids with intestinal failure


UCLA study finds promising results with fish oil.

Isabella Piscione following her fish oil treatment

Isabella Piscione following her fish oil treatment

Children who suffer from intestinal failure, most often caused by a shortened or dysfunctional bowel, are unable to consume food orally. Instead, a nutritional cocktail of sugar, protein and fat made from soybean oil is injected through a small tube in their vein.

For these children, the intravenous nutrition serves as a bridge to bowel adaptation, a process by which the intestine recovers and improves its capacity to absorb nutrition. But the soybean oil, which provides essential fatty acids and calories, has been associated with a potentially lethal complication known as intestinal failure–associated liver disease, which may require a liver and/or intestinal transplant. Such a transplant can prevent death, but the five-year post-transplant survival rate is only 50–70 percent.

Previous studies have shown that replacing soybean oil with fish oil in intravenous nutrition can reverse intestinal failure–associated liver disease. However, the necessary duration of fish oil treatment had not been established in medical studies.

Now, a clinical trial conducted at the Children’s Discovery and Innovation Institute at Mattel Children’s Hospital UCLA has found that, compared with soybean oil, a limited duration (24 weeks) of fish oil is safe and effective in reversing liver disease in children with intestinal failure who require intravenous nutrition. The researchers believe that fish oil may also decrease the need for liver and/or intestinal transplants — and mortality — associated with this disease.

The researchers’ study, “Six Months of Intravenous Fish Oil Reverses Pediatric Intestinal Failure Associated Liver Disease,” is published online in the Journal of Parenteral and Enteral Nutrition.

“With this particular study, we set out to determine if a finite period of six months of intravenous fish oil could safely reverse liver damage in these children, and we have had some promising results,” said lead author Dr. Kara Calkins, an assistant professor in the department of pediatrics in the division of neonatology and developmental biology at UCLA. “But because intravenous fish oil is not yet approved by the Food and Drug Administration and is much more costly than soybean oil, it is typically not covered by insurance. As a result, this oil is considered experimental and is currently available only under special protocols. If it proves safe and effective for patients, we hope it would eventually be available for wider use.”

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Discovery could improve liver transplant success


Natural substance found in blood vessels stimulates organ and tissue regeneration.

Bruce Hammock, UC Davis

Bruce Hammock, UC Davis

Researchers from multiple institutions, including UC Davis and Harvard Medical School, have discovered a novel and natural means that could increase the success of human liver transplants and speed the recovery of both the patient and the donor.

The study is especially significant because of the desperate shortage of livers among thousands of very ill patients, said lead researcher Dipak Panigrahy of Harvard Medical School, in work published online in the July 29 edition of Proceedings of the National Academy of Sciences (PNAS).

According to the American Liver Foundation website, 1,848 patients died in 2005 while waiting for a donated liver to become available. “Currently, about 17,000 adults and children have been medically approved for liver transplants and are waiting for donated livers to become available. The waiting list grows every year.”

The researchers found that a natural substance in blood vessels stimulates organ and tissue regeneration.

“The endothelium of blood vessels generate the lipid mediators called epoxyeicosatrienoic acids or EETs,” explained Panigrahy, assistant professor of pathology at Harvard Medical School and the Center of Vascular Biology Research at the Beth Israel Deaconess Medical Center, Boston. “EETs stimulate blood vessel formation, and organ regeneration is dependent on blood vessel formation. However, the role of EETs in organ regeneration is unknown. Our research shows that EETs stimulate organ and tissue regeneration.”

The 28-member discovered that “systemic administration of EETs significantly increased liver and lung regeneration by 23 percent to 46 percent when compared to control mice post partial liver resection,” Panigrahy said.

“This can be very useful in transplant both for the donor and the recipient in getting full function back with liver transplant,” said researcher and co-author Bruce Hammock, a distinguished professor of entomology with a joint appointment at the UC Davis Comprehensive Cancer Center.

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Free hepatitis B screenings offered on May 19


UC Davis event targets Asian-American adults.

A UC Davis medical student prepares to draw blood for hepatitis screening test.

Asian Americans and adult children of foreign-born Asian Americans are invited to a free hepatitis B screening event Sunday (May 19) at the UC Davis Comprehensive Cancer Center.

The event, from 10 a.m. to 2 p.m., is being held in recognition of Asian Pacific Islander Heritage Month and National Hepatitis Testing Day. It is funded with a federal grant aimed at boosting hepatitis B screening and preventing liver cancer in the Asian-American community.

“Our goal is to screen 1,000 foreign-born or children of foreign-born Asian Americans who are 18 years of age or older, and who are from areas where hepatitis B is endemic,” said Julie Dang, a community health program supervisor at the UC Davis Comprehensive Cancer Center and study program manager.

One of every 10 Asian Pacific Islanders has hepatitis, and most do not know they have been infected because often there are no symptoms. Untreated, hepatitis B virus can lead to liver cancer. Nearly 80 percent of liver cancer cases in Asian Americans can be directly traced to the Hepatitis B virus infection.

Screening participants who test negative and need vaccination will be put on a waiting list and contacted when vaccines become available.  All participants will receive a phone call and a result letter regarding their status.

“Individuals who test positive will receive individual counseling sessions to help them understand their status and get referrals for  care,” said Dang.

Additional event offerings will include risk-factor screenings (hepatitis C, diabetes and blood pressure), health education and light refreshments. All participants will receive a $10 Walmart gift card for their contribution to the study.

The event is co-sponsored by the Asian American Network for Cancer Awareness, Research and Training (AANCART), a national organization that is headquartered at the cancer center

The UC Davis Comprehensive Cancer Center is at 4501 X St. in Sacramento. To RSVP for the event, please contact Tina Fung at (916) 734-5371, or email her at tina.fung@ucdmc.ucdavis.edu.

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Home-based health visits increase hepatitis screening rates for Hmong Americans


First-of-kind study finds effectiveness of health care worker visits.

Twenty-four percent of Hmong study subjects who learned about hepatitis B and liver cancer were later screened.

In the first study of its kind, lay health workers increased screening rates for hepatitis B virus (HBV) and knowledge about the disease among a group of Asian Americans, known as the Hmong, UC Davis researchers have found. The study appears online today (April 23) in Cancer Epidemiology, Biomarkers & Prevention.

Hmong Americans, who originate from the mountainous areas of Laos, are at elevated risk for chronic hepatitis B — the major risk factor for liver cancer. They’re also at greater risk than either white or other Asian Americans for poor outcomes from liver cancer.

Although Hmong Americans often have health insurance, cultural and language barriers can prevent access to adequate screening for hepatitis B and liver cancer,  according to study author Moon Chen Jr., professor and associate director for cancer control at UC Davis, who led the research effort.

“Compared to other Asian Americans, liver cancer tends to be found at a later stage among the Hmong, and the survival rate is very low. While the overall survival rate for liver cancer is 10 percent, Hmong people who are diagnosed with the disease usually live for less than a year, and often for as little as a month or two,” said Chen.

“We wanted to decrease the probability of earlier death from liver cancer among the Hmong and increase the probability of earlier detection,” said Chen, who is also principal investigator for the Asian American Network for Cancer Awareness Research and Training (AANCART), the National Cancer Institute’s National Center for Reducing Asian American Cancer Health Disparities.

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Teen liver transplant recipient to honor donor at 2013 Rose Parade


Alfonso Garcia is spreading the word about the value of organ donation.

Alfonso Garcia and his parents pose with the UCSF medical team that cared for him during his 2010 life-saving liver transplant.

Alfonso Garcia still carries around a baseball cap that belonged to a 22-year-old man who passed away in 2010 having never met him. But the cap is just a small token of an even bigger reminder that the 18-year-old college freshman carries with him every day: the man’s liver, which saved Garcia’s life.

Since receiving the liver transplant at UC San Francisco, Garcia has made it a mission to spread the word about the value of organ donation by sharing the memory of his hero, George Becker, who died after a bad sinus infection spread to his brain.

Years later, Garcia still “thinks about George every day,” he said. “I don’t take anything for granted.”

As part of that mission, Garcia was selected by UCSF and the California Transplant Donor Network to ride on the Donate Life “Journeys of the Heart” float at the 2013 Tournament of Roses Parade in Pasadena on Tuesday, Jan. 1., in honor of Becker. The float will bear a florograph of Becker – a portrait made of flowers.

Garcia – whose father, Oscar Garcia, is a respiratory therapist at UCSF – was 15 years old when he was diagnosed with Wilson’s disease, a genetic disorder in which too much copper accumulates in the body’s tissues, causing damage to the liver and nervous system. His health was deteriorating quickly and he needed a liver transplant immediately.

Becker, who signed up to be an organ donor on his driver’s license when he was 16, ended up being the right match. And Garcia’s UCSF medical team – which included transplant surgeon Ryutaro Hirose, M.D.; Philip Rosenthal, M.D., medical director of the Pediatric Liver Transplant Program; Emily Perito, M.D., a clinical fellow in pediatrics and gastroenterology; and nurse practitioner Susan Diaz, M.S.N. – performed a successful transplant.

“It’s something that I appreciate and hold very close to my heart, the people at UCSF,” said Garcia, now a healthy, strong young man who just started attending the University of San Francisco. “Growing up, seeing my dad go to work every day, I didn’t know the significance of that until the day I was under the care of UCSF. I was like, ‘Wow, these people do an incredible job day in and day out to care for people and save people’s lives.’”

Recognized as a world leader in organ transplantation since 1964, the UCSF Organ Transplant Service has performed transplants for more than 10,000 patients and has played a key role in defining the field. The UCSF Liver Transplant Program, designated as a “Center of Excellence” by the U.S. Department of Health and Human Services, performs more liver transplants than any other hospital in Northern California – more than 2,300 liver transplants for adults and children since it began in 1988.

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Related link:
Rose Parade tribute to a Bruin who saved lives

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Gene found that turns carbs into fat


UC Berkeley discovery could provide new target for treatments.

Fatty liver tissue

Image courtesy of The Sul Lab

A gene that helps the body convert that big plate of holiday cookies you just polished off into fat could provide a new target for potential treatments for fatty liver disease, diabetes and obesity.

Researchers at the University of California, Berkeley, are unlocking the molecular mechanisms of how our body converts dietary carbohydrates into fat, and as part of that research, they found that a gene with the catchy name BAF60c contributes to fatty liver, or steatosis.

In the study, to be published online Dec. 6 in the journal Molecular Cell, the researchers found that mice that have had the BAF60c gene disabled did not convert carbohydrates to fat, despite eating a high-carb diet.

“This work brings us one step forward in understanding fatty liver disease resulting from an excessive consumption of carbohydrates,” said the study’s senior author, Hei Sook Sul, professor at UC Berkeley’s Department of Nutritional Science and Toxicology. “The discovery of this role of BAF60c may eventually lead to the development of treatment for millions of Americans with fatty liver and other related diseases.”

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Most liver transplant candidates receive donation offers


UCSF study finds transplant wait-list deaths are not just due to organ availability.

Jennifer Lai, UC San Francisco

Most liver transplant candidates who died or were removed from the transplant list actually received one or more liver donation offers, according to a recent UC San Francisco study.

“What we found challenges the simplistic view that transplant dynamics are driven simply by organ availability,” said lead author, Jennifer Lai, M.D., assistant clinical professor in the UCSF Division of Gastroenterology and Hepatology. “Efforts to reduce wait-list mortality must target all aspects of mismatch between supply and demand.” 

Recognized as a world leader in organ transplantation since 1964, the UCSF Organ Transplant Service has performed transplants for more than 10,000 patients and has played a key role in defining the field. The UCSF Liver Transplant Program, designated as a “Center of Excellence” by the U.S. Department of Health and Human Services, performs more liver transplants than any other hospital in Northern California – over 2,300 liver transplants for adults and children since it began in 1988.

For this study, the research team analyzed data from 33,389 candidates listed in the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) registry during the time frame of Feb. 1, 2005, to Jan. 31, 2010. Out of the candidates who had died or been delisted, 84 percent received one or more liver offers prior to death/delisting, indicating that they had an opportunity to undergo transplantation. Reasons for liver offer refusals were reported as donor quality/age or other donor-related factors, size compatibility or recipient readiness.

“Understanding the real-time factors involved in the decisions regarding liver transplant offers is vital to improving the wait-list process,” said senior author, John Roberts, M.D., professor of surgery and chief of the UCSF Division of Transplantation. “While some of the factors are beyond control, others can be managed.”

Simply increasing the availability of deceased donor livers or the number of offers may not necessarily reduce wait-list mortality, according to the study, published in the leading journal in its field, Gastroenterology. Instead, the study suggests that efforts must be made to understand multiple factors involving candidates, donors and transplant centers to help influence what is often a complex and dynamic decision to accept or decline a liver offer.

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