Nav: Home

Study: Two enzymes control liver damage in NASH

February 06, 2020

As much as 12 percent of adults in the United States are living with nonalcoholic steatohepatitis (NASH), an aggressive condition that can lead to cirrhosis or liver cancer. After identifying a molecular pathway that allows NASH to progress into liver cell death, University of California San Diego School of Medicine researchers were able to halt further liver damage in mouse models with NASH.

"We know that fatty liver causes inflammation and scarring in the organ and that it progresses to cirrhosis, liver cancer and liver failure," said senior author Alan Saltiel, PhD, director of the UC San Diego Institute for Diabetes and Metabolic Health. "What has never been clear is the trigger that allows the transition from chronic inflammation to cell death. We now see that there is a linear progression to liver failure and we found a way to stop it in mice."

The switch, report researchers in the February 7, 2020 online edition of Science, comes from the suppression of the enzyme AMPK, one of the master regulators of energy expenditure, and the increase in activity of caspase-6, an enzyme involved in apoptosis or programmed cell death.

When AMPK activity is low, a cell's ability to burn calories decreases, resulting in fat storage. The team fed mice a high-fat diet and turned AMPK off, expecting that their fatty liver condition would worsen, but it did not. However, progression to NASH and liver failure did.

"We were surprised to see that manipulating AMPK did not dramatically regulate metabolism as we presumed it would, but rather it seemed to be regulating something in transition from fatty liver to NASH and from NASH to hepatocellular cell death," said Saltiel. "In this case, AMPK acted as a sensor, keeping cell death in check. When AMPK activity was lost, cell death proceeded unchecked. It turns out that AMPK blocks activity of caspase-6, so when AMPK activity drops, caspase-6 is unleashed, acting as a death signal for liver cells."

Armed with this new understanding of the roles of AMPK and caspase-6, the team applied an AMPK activator, decreasing caspase-6 activity. While this action did not halt fatty liver, it did stop progression from fatty liver to NASH and subsequent liver cell death. The same result occurred when the team used a caspase-6 inhibitor.

"Caspase-6 was elevated in both mouse models and in samples from human patients who have NASH," said Saltiel. "Our study identifies two possible targets for putting the brakes on further liver damage. Both AMPK activators and caspase-6 inhibitors prevented the molecular pathway leading to sustained liver cell death."

The team is now developing caspase-6 inhibitors for further testing.
-end-
Human patient samples were provided by Rohit Loomba, MD, professor of medicine in the Division of Gastroenterology and director of the NAFLD Research Center at UC San Diego, which is helping shape new therapies for the treatment of NASH.

NASH refers to a disease that causes inflammation and scarring in the liver. Over time, this can result in permanent hardening of the liver tissues, the last stage of liver disease known as cirrhosis. At the point cirrhosis develops, the liver struggles to perform normal functions, which can cause serious illness and death. While it resembles alcoholic liver disease, NASH occurs in people who drink little or no alcohol.

The Liver Center at UC San Diego Health is the region's leader in the treatment of acute and chronic liver diseases. The team, including Loomba, specialize in treating people living with NASH.

Co-authors include: Peng Zhao, Xiaoli Sun, Cynthia Chaggan, Zhongji Liao, Kai in Wong, Feng He, Seema Singh, Michael Karin and Joseph L. Witztum, all at UC San Diego.

Disclosures: Alan Saltiel and Peng Zhao are named inventors of a patent application related to the use of AMPK and caspase-6 as therapeutic targets for NASH. Joseph L. Witztum receives royalties from patents owned by UC San Diego on oxidation-specific antibodies and of biomarkers related to oxidized lipoprotein. He is a co-founder and has an equity interest in Oxitope, Inc., and Kleanthi Diagnostics, LLC. Witztum is also a consultant to Ionis Pharmaceuticals.

University of California - San Diego

Related Liver Cancer Articles:

New liver cancer research targets non-cancer cells to blunt tumor growth
'Senotherapy,' a treatment that uses small molecule drugs to target ''senescent'' cells, or those cells that no longer undergo cell division, blunts liver tumor progression in animal models according to new research from a team led by Celeste Simon, PhD, a professor of Cell and Developmental Biology in the Perelman School of Medicine at the University of Pennsylvania and scientific director of the Abramson Family Cancer Research Institute.
Liver cancer: Awareness of hepatitis D must be raised
Scientists from the University of Geneva (UNIGE) and the Geneva University Hospitals (HUG) have studied the most serious consequence of chronic hepatitis: hepatocellular carcinoma.
A new treatment for liver cancer
In the latest issue of Molecular Therapy, Skoltech and MIT researchers have published a new combinatorial therapy for the treatment of liver cancer.
New study indicates exercise can help prevent liver cancer
Liver cancer is the fourth most common cause of cancer death worldwide and is growing rapidly due to the 'diabesity pandemic.' A new study reported in the Journal of Hepatology, published by Elsevier, provides strong evidence that voluntary exercise could help prevent the most common type of liver cancer, hepatocellular carcinoma, and identifies the molecular signaling pathways involved.
From obesity to liver cancer: Can we prevent the worst?
Hepatocellular carcinoma, a liver cancer linked to the presence of fat in the liver, is one of the leading causes of cancer death worldwide.
Liver cancer deaths climb by around 50% in the last decade
Liver cancer deaths have increased by around 50% in the last decade and have tripled since records began, according to the latest calculations by Cancer Research UK.
NUS researchers show potential liver cancer treatment by targeting cancer stem-like cells
NUS researchers from the Cancer Science Institute of Singapore and the N.1 Institute for Health have shown the potential use of small molecule inhibitors to treat advanced liver cancer.
Breast cancer gene a potential target for childhood liver cancer treatment
Hepatoblastoma is a rare liver cancer that mainly affects infants and young children and is associated with mutations in the β-catenin gene.
Blood transfusion during liver cancer surgery linked with higher risk of cancer recurrence and death
Receiving a blood transfusion during curative surgery for the most common type of liver cancer (hepatocellular carcinoma) is associated with a much higher risk of cancer recurrence and dying prematurely, according to new research being presented at this year's Euroanaesthesia congress.
Blocking platelets: A possible option to prevent fatty liver disease and liver cancer
Blood platelets which interact with liver cells and immune cells play a major role in the development of fatty liver disease, non-alcoholic fatty liver inflammation and liver cancer, scientists from the German Cancer Research Center (DKFZ) in Heidelberg and from Zurich University and University Hospital have now shown in a publication.
More Liver Cancer News and Liver Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.