{"doi":"10.1016/j.jcmgh.2023.04.008","title":"Liver Fat – Gone, but Not Forgotten?","abstract":"Nonalcoholic fatty liver disease (NAFLD) is a prominent complication of obesity wherein ectopic lipid deposits accumulate in the liver. A subset of patients with liver fat will go on to develop nonalcoholic steatohepatitis (NASH), fatty liver complicated by inflammation that progresses to fibrosis and then cirrhosis, followed by overt liver failure and/or the development of hepatocellular carcinomas. The metabolic abnormalities that occur during NAFLD, the trigger that leads to the onset of NASH, and the timing and degree of reversibility after fat clearance remain incompletely understood. A major barrier to progress in these areas has been the lack of adequate in vitro models because the development of NAFLD in human beings or even in rodents is variable and time consuming, taking place over many months to years. In this issue, Fan et al1Fan Cell Mol Gastroenterol Hepatol. 2023; Google Scholar report the development of a culture system that allows the maintenance of human hepatocytes for more than 2 weeks, with the ability to induce or reverse fat accumulation based on the presence of free fatty acids in the medium. To avoid creating a barrier on top of the hepatocytes while still maintaining a “sandwich” configuration to promote the retention of function, media was supplemented daily with 2% Geltrex. Despite the shorter time course and simplified culture model, fat accumulation in hepatocytes was pronounced and accompanied by disruption to the cytoskeletal network. This is an important step forward in the development of an in vitro model that mimics hepatocyte fat accumulation. Moreover, fat droplets were accompanied by an increase in mitochondrial respiratory capacity, drawing parallels to increased respiratory capacity in liver biopsy specimens from obese human beings (with or without NAFLD),2Koliaki C. Szendroedi J. Kaul K. et al.Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.Cell Metab. 2015; 21: 739-746Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar and an increase in mitochondrial oxidative metabolism shown using in vivo tracing in subjects with NAFLD.3Sunny N.E. Parks E.J. Browning J.D. et al.Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease.Cell Metab. 2011; 14: 804-810Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar This early increase in mitochondrial respiratory capacity in the presence of fat likely reflects an adaptive response because the hepatocytes were able to maintain urea and albumin production and displayed enhanced resistance to hydrogen peroxide–induced oxidative stress. Upon removal of free fatty acids from the medium, fat droplets were cleared rapidly and cytoskeletal rearrangements were reversed. However, mitochondrial respiratory capacity remained increased. In contrast to the enhanced oxidative stress resistance observed in the presence of fat droplets, hepatocytes that had recovered from steatosis were more sensitive to oxidative stress induced by hydrogen peroxide. This might imply that excess mitochondrial capacity becomes a liability in the absence of metabolic demand, and raises the possibility that recovery from early stage NAFLD might be accompanied by a period of increased risk and susceptibility to other metabolic stressors. Although the present study establishes a useful system for further investigations and raises some interesting observations, it also had some limitations. First, the hepatocytes studied came from a total of 3 human donors, meaning that further work will be needed to establish the consistency of these behaviors. Second, it remains to be shown that the increase in mitochondrial respiration observed in culture was related mechanistically to the increase in mitochondrial respiration observed in vivo. Whether this reflects a simple increase in mitochondrial mass or changes in the expression or activity of specifi","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2023,"id":407499,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":231765,"name":"Joseph A. Baur","orcid":"0000-0001-8262-6549","position":1,"is_corresponding":false},{"id":311279,"name":"Paul M. Titchenell","orcid":"0000-0002-9941-5649","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T01:21:10.867368Z","pmid":"37224913","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}