Nonalcoholic fatty liver disease (NAFLD) is an epidemic affecting 30% of the US population.
NAFLD is characterized by insulin resistance and by defective lipid metabolism and
mitochondrial dysfunction in the liver. SLC25A34 is a major repressive target of miRNA-122,
a miRNA that has a central role in NAFLD and liver cancer. However, little is known
about the function of SLC25A34. To investigate SLC25A34 in vitro, mitochondrial respiration and bioenergetics were examined using hepatocytes depleted
of Slc25a34 or overexpressing Slc25a34. To test the function of SLC25A34 in vivo, a hepatocyte-specific knockout mouse was generated, and loss of SLC25A34 was assessed
in mice maintained on a chow diet and a fast-food diet (FFD), a model for NAFLD. Hepatocytes
depleted of Slc25a34 displayed increased mitochondrial biogenesis, lipid synthesis, and ADP/ATP ratio;
Slc25a34 overexpression had the opposite effect. In the knockout model on chow diet, SLC25A34
loss modestly affected liver function (altered glucose metabolism was the most pronounced
defect). RNA-sequencing revealed changes in metabolic processes, especially fatty
acid metabolism. After 2 months of FFD, knockouts had a more severe phenotype, with
increased lipid content and impaired glucose tolerance, which was attenuated after
longer FFD feeding (6 months). This work thus presents a novel model for studying
SLC25A34 in vivo in which SLC25A34 plays a role in mitochondrial respiration and bioenergetics during
NAFLD.
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Article Info
Publication History
Published online: June 16, 2022
Accepted:
June 8,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Supported by grants from the NIH ( R01 DK103645 ), Commonwealth of Pennsylvania, and University of Pittsburgh Physicians Foundation (A.W.D); the Hemophilia Center of Western Pennsylvania and NIH ( R01HL133003-01A1 ) (S.S.); NIH ( R01 DK122990 ) (B.B.); and NIH - NIBIB training grant ( T32 EB001026 ) entitled “Cellular Approaches to Tissue Engineering and Regeneration” (S.R.W.). Additional support provided by the Pittsburgh Liver Research Center Clinical Biospecimen Repository and Processing Core ( P30 DK120531 ); the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource, which is supported in part by award P30CA047904 from the NIH; and the Center for Metabolism and Mitochondrial Medicine , which is supported in part by the Pittsburgh Foundation ( MR2020 109502 ).
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© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
