NEW YORK (Reuters Health) – For the first time, acquired (somatic) mutations that impact metabolism and insulin sensitivity were identified in liver cells of patients with chronic liver disease in a genomics study.
“Mutations in the liver mostly arise randomly throughout a person’s life, just with the normal aging process, but we know that certain factors such as smoking, chronic alcohol consumption, and other toxins can increase someone’s mutation rate,” Dr. Peter Campbell of the Wellcome Sanger Institute in Hinxton, UK, told Reuters Health by email.
“We found that these naturally arising mutations in the liver could protect those liver cells from damage caused by the disease process,” he said. “What we will be excited to follow up is whether these mutations contribute to metabolic diseases such as type 2 diabetes by enabling the liver cells to shirk their normal duties in processing dietary sugars and fats.”
“This is the first time a link has been found connecting metabolic diseases with mutations acquired during someone’s life – as opposed to inherited genetic changes – allowing us to propose an exciting new model of systemic disease,” he added.
In their Nature report, Dr. Campbell and colleagues note that progression of chronic liver disease to hepatocellular carcinoma (HCC) is caused by the acquisition of somatic mutations that affect 20-30 cancer genes. In the current study, they analyzed somatic mutations from 1,590 genomes across 34 liver samples from patients with alcohol-related liver disease (ARLD), non-alcoholic fatty liver disease (NAFLD), and neither condition (controls).
Separately, they accessed mutation calls for 1,670 HCCs reported in the International Cancer Genome Consortium data portal.
Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signaling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1.
Six of the seven patients with FOXO1S22W hotspot mutations had convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient.
CIDEB, which regulates lipid droplet metabolism in hepatocytes, and GPAM, which produces storage triacylglycerol from free fatty acids, also showed a significant excess of mutations. As with FOXO1, convergent evolution was frequent – up to 14 independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations.
Metabolism gene mutations were distributed across multiple segments of the liver and increased clone size; they were seen in both ARLD and NAFLD, but rarely in HCC.
The authors state, “A major theme emerging from our study is the contrast of within-patient convergence with between-patient divergence. Within the liver of one patient, we observed many independent hepatocyte clones preferentially expanding with mutations in the same metabolism gene. Across different patients, however, there was considerable heterogeneity in both the frequency of driver mutations and which genes they affected. Further studies in larger clinical cohorts will be required to understand whether this patient-to-patient heterogeneity results from different subtypes of disease; whether it informs on disease severity; and whether it predicts future risk of cancer or liver failure.”
Dr. Brian Finck, Professor of Medicine at Washington University in St. Louis commented on the study in an email to Reuters Health. “There are several avenues by which these studies could lead to new treatments for NAFLD and NASH,” he said, including identifying mutations in genes not previously suspected to confer resistance to NAFLD, which might lead to drugs that target the gene products, or genetic therapies for the liver.
“Furthermore,” he noted, “as the cost of the analyses needed to check for these mutations comes down, this could lead to personalized medical treatments based on which mutations are prevalent in the liver of an individual patient.”
“The cause and effect relationship between the mutations and the disease is not entirely clear,” he noted. “It’s hypothesized that these mutations confer a survival advantage that allows hepatocytes to proliferate and replace dead or dying cells. However, until we know whether the cells that have the mutations are protected from accumulating lipid, this is only a presumption.”
“The finding that these patients had a several different mutations in the same gene raises a number of larger questions regarding the rates of genetic mutations in the normal liver,” he added. “Do NAFLD or ARLD disease conditions lead to an increased rate of mutation? Is the rate of mutation normally high in the liver, but mutant cells fail to proliferate because there is no survival advantage? Are these mutant cells identified and eliminated by the body’s homeostatic mechanisms?”
SOURCE: https://go.nature.com/2Ze8JqS Nature, online October 13, 2021.
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