Replenishing Hepatocytes

Research Highlights

LIVER GENETICS Replenishing An HSD17B13 variant reduces cirrhosis risk hepatocytes A newly identified gene variant reduces risk decreased ALT and AST levels. The variant New research provides insights into hepatocyte of chronic liver disease (CLD) and cirrhosis, allele (allele frequency 26%) was also negatively renewal during maintenance and repair, with according to a new study. associated with CLD: in heterozygotes, risk of the identification of a subset of hepatocytes CLD and cirrhosis are important global alcoholic cirrhosis and nonalcoholic cirrhosis expressing telomerase (TERTHigh hepatocytes) causes of morbidity and mortality. Whereas was decreased 42% and 26% respectively; for that can repopulate the liver during homeostasis the environmental factors contributing to the homozygotes, the respective risk reductions and after injury. development and progression of CLD, such as were 73% and 49%. Notably, the variant was Understanding the mechanisms of liver alcohol and viral hepatitis, are well-understood, not associated with simple steatosis, suggesting regeneration has been an intense area of a large proportion of the genetic risk that it mitigates CLD progression. research, particularly with respect to the cellular component is either unexplained or poorly Functional analyses revealed that sources that maintain and repair the liver. characterized. For instance, the mechanisms HSD17B13 was enriched on membranes Existing evidence linked telomerase to long-term underlying the association between PNPLA3 surrounding lipid droplets in human renewal in stem cells, and germline inactivating sequence variance and increased risk of hepatocyte cell lines. The HSD17B13 variant mutations in telomerase genes have been NAFLD and cirrhosis remain unclear a decade was found to alter mRNA splicing, yielding shown to predispose mice and humans to after this relationship was first reported. a truncated protein with reduced enzymatic liver cirrhosis. Given these observations, To identify additional genetic associations activity against the experimentally determined Lin et al. reasoned that telomerase expressed with CLD, Abul-Husn and colleagues tested enzymatic substrates of HSD17B13, steroids in liver cells could have unique properties and exome sequence data from 46,544 individuals (such as estradiol) and bio-active lipids (such 2 wanted to characterize this particular subset (median BMI 30 kg/m ) for associations as leukotriene B4). These findings suggest that of cells. between single-nucleotide polymorphisms and modulating HSD17B13 activity could be a Using a series of experiments in mice serum levels of alanine aminotransferase (ALT) therapeutic target for treating CLD. (including lineage tracing analysis), the and aspartate aminotransferase (AST). This Hugh Thomas researchers identified TERTHigh hepatocytes analysis uncovered a novel association between Original article Abul-Husn, N. S. et al. A protein-truncating a variant in HSD17B13, which encodes HSD17B13 variant and protection from chronic liver disease. throughout the liver, representing 3–5% of N. Engl. J Med. 378, 1096–1106 (2018) hepatocytes. Crucially, during homeostasis, hydroxysteroid 17-β dehydrogenase 13, and they found that this subset of liver cells could repopulate the liver, comprising ~30% of PANCREATIC CANCER the liver at 1 year. Moreover, these TERTHigh hepatocytes were distributed throughout all lobular zones (the majority located in Microbiome promotes pancreatic cancer the periportal and midlobular areas), and yielded According to a new study, the cancerous In preinvasive and invasive mouse models of expanding hepatocyte clones by a self-renewal pancreas in mice and humans harbours an PDAC, bacterial ablation using germ-free mice or and differentiation mechanism. abundant microbiota that promotes immune antibiotics was shown to protect against PDAC After chemical injury (a single dose of carbon suppression and oncogenesis. growth and was associated with immunogenic tetrachloride damaging the liver periportal Few studies have established a link between reprogramming of the tumour microenvironment. zone), repopulation by TERTHigh hepatocytes was the gut microbiota and carcinomas in organs The decrease in select Toll-like receptor accelerated and their progeny could cross zonal separate from the gastrointestinal tract. activation on monocytic cells led to increased boundaries during repair. Furthermore, these “In pancreatic ductal adenocarcinoma (PDAC), tumour-protective M1 macrophage polarization, cells contributed to hepatocyte regeneration we previously reported that activation of pattern which promoted infiltration and activation of after diet-induced liver injury, and genetic recognition receptors accelerates tumorigenesis T helper cells and cytotoxic T cells. ablation of TERTHigh cells combined with diet- via induction of innate and adaptive immune Bacterial ablation also upregulated T-cell induced injury resulted in a marked increase in suppression,” explains author Mautin Hundeyin. PD1 expression, suggesting an approach hepatic stellate cell activation and liver fibrosis “Therefore, we hypothesized that microbial that could synergize with checkpoint-based in the mice. dysbiosis can drive PDAC progression by immunotherapy. “Based on this finding, we promoting immune tolerance and targeting the are starting a clinical trial where patients with The authors propose a ‘distributed model’ microbiome can reverse this process.” locally advanced PDAC will receive antibiotics to explain hepatocyte renewal. “According to Using 16 S ribosomal RNA fluorescent probes and pembrolizumab prior to resection,” this model, rare TERTHigh hepatocytes located and quantitative PCR, a 1,000-fold increase in concludes Hundeyin. The data also suggest that throughout the lobule form enlarging clones intrapancreatic bacteria was found in human elements of the microbiota might be useful in during homeostasis in response to hepatocyte PDAC compared with normal pancreatic tissue. PDAC diagnosis. loss, and this response is accelerated during liver Select bacteria were increased in PDAC compared Iain Dickson injury,” they write. with the gut and were found to translocate via the Katrina Ray pancreatic duct. “This was an interesting finding Original article Pushalkar, S. et al. The pancreatic cancer Original article Lin, S. et al. Distributed hepatocytes as the pancreas has traditionally been considered microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. , 403–416 (2018) expressing telomerase repopulate the liver in homeostasis and a sterile organ,” says Hundeyin. 8 injury. Nature 556, 244–248 (2018)