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UCLA researchers have demonstrated that a key regulator of cholesterol and fat metabolism in the liver also plays an important role inthe development of liver fibrosis the build-up of collagen scartissue that can develop into cirrhosis . Cirrhosis, in turn, is a major cause of premature death and isincurable without a liver transplant. Published in the March issue of the journal Gastroenterology, thestudy shows that liver X receptors (LXRs), master regulators ofcholesterol, fat and inflammatory gene expression, also control thefibrosis-making cells of the liver, known as hepatic stellatecells. In the face of chronic liver injury due to excess fat, chronicviral hepatitis or alcohol abuse, for example stellate cells become activated andlaunch an inflammatory and fibrotic cascade that eventually resultsin the build-up of collagen scar tissue in the liver. LXRs, when stimulated, "turn on" several hundred genes that holdinstructions to create proteins for carrying out bodily processesin cells, from transporting and excreting cholesterol tosynthesizing fat in the liver. They have also been shown tosuppress inflammatory processes in several contexts. "Our work sets the stage for looking at new ways to modulatecholesterol and/or fat metabolism in order to have therapeuticpotential for the treatment of fibrosing liver diseases," said leadauthor Dr. Simon Beaven, an assistant professor of digestivediseases at the David Geffen School of Medicine at UCLA. The research was done in the laboratory of senior author Dr. PeterTontonoz, a professor of pathology and laboratory medicine at theGeffen School of Medicine and a Howard Hughes Medical Instituteinvestigator. Beaven noted that the recent rise in obesity has resulted in a surge in the prevalence of a condition known asfatty liver, which can be a precursor to fibrosis and chronic liverdisease. Simple fatty liver, also known as non-alcoholic fattyliver disease, or NAFLD, is one of the most common reasons patientsconsult a liver doctor in the United States. Cirrhosis due to fattyliver is skyrocketing and within a decade may become the mostcommon indication for liver transplantation. Beaven said the need to find better treatments for liver disease iscrucial. "A 'holy grail' for liver researchers is to develop anti-fibrotictreatments that target activated stellate cells in order to slow orprevent the development of cirrhosis," Beaven said. "Our studyoffers the first detailed look at how LXRs specifically impact theactivation of hepatic stellate cells and the subsequent developmentof liver fibrosis in animal models." UCLA researchers have found that LXRs normally play a role inhelping to reduce the collagen-producing actions of stellate cellswhen the cells are "activated" by liver damage. For the study, UCLAscientists first tested how activated stellate cells taken frommice would react when a chemical that induces LXR activity wasadded to the cell culture. In stellate cells from normal mice, LXRs suppressed theinflammatory and fibrosis-promoting program. But in those takenfrom mice genetically lacking LXRs, that same program of genessignificantly increased because the inhibitory effect of LXRs wasno longer present. "We showed that LXRs dampen stellate cell activation by repressinginflammatory and collagen-producing genes," Beaven said. To further gauge the strength of the response, scientists took themedium from the cultures of LXR-deficient cells and added it tostellate cells from normal mice. These cells then showed a markedlyexaggerated inflammatory and collagen-producing response,suggesting that LXR-deficient stellate cells are secreting signalsto promote fibrosis. The researchers noted that these experiments demonstrate that LXRscontrol a fibrotic response in stellate cells that can have a wideinfluence on neighboring cells. The scientists also found that after replicating chronic liverinjury, mice without LXRs had dramatically more liver fibrosis thannormal mice. "The genetic loss of LXRs rendered the mice susceptible todeveloping fibrotic liver disease," Beaven said. But LXRs are also known to have important functions in the immunesystem. The researchers then wanted to know whether the effectsthey were seeing in animals were due to changes in stellate cellactivity specifically or whether immune cells derived from bonemarrow accounted for most of the effect. After extensive testing,the researchers found no differences in the level of liver fibrosis among normal mice and animalslacking LXRs, suggesting that the contribution from the immunesystem was negligible. "This finding, along with the cell culture studies, suggests thatLXRs' influence on fibrosis most likely resides in alteringstellate cell function in the liver," Beaven said. "This is acritical finding and opens an entire new field of study forstellate cell biologists." Additional studies will further identify which genes in stellatecells are activated by LXRs and help researchers better understandthe role of cholesterol metabolism in the fibrotic response. This study was funded primarily by grants from the NationalInstitutes of Health and the Howard Hughes Medical Institute.Collaborators from the University of Southern California werefunded by core grants from the NIH and the Southern CaliforniaResearch Center for ALPD and Cirrhosis. Other study authors included senior investigator Dr. Peter Tontonozof the Howard Hughes Medical Institute; Kevin Wroblewski andCynthia Hong from Tontonoz's lab; Jiaohong Wang and Hide Tsukamotoof the Southern California Research Center for ALPD and Cirrhosis,USC's Keck School of Medicine and the Department of VeteransAffairs Greater Los Angeles Healthcare System; and Steven Bensingerof the department of pathology at the David Geffen School ofMedicine at UCLA. Source: University of California, Los Angeles (UCLA) Additional References Citations. The e-commerce company in China offers quality products such as Dutch Wire Mesh Manufacturer , China Spiral Welded Pipe, and more. For more , please visit Welding Wire Mesh today!
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