Deletion of NLRX1 increases fatty acid metabolism and prevents diet-induced hepatic steatosis and metabolic syndrome

Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1883-1895. doi: 10.1016/j.bbadis.2018.03.003. Epub 2018 Mar 4.


NOD-like receptor (NLR)X1 (NLRX1) is an ubiquitously expressed inflammasome-independent NLR that is uniquely localized in mitochondria with as yet unknown effects on metabolic diseases. Here, we report that NLRX1 is essential in regulating cellular metabolism in non-immune parenchymal hepatocytes by decreasing mitochondrial fatty acid-dependent oxidative phosphorylation (OXPHOS) and promoting glycolysis. NLRX1 loss in mice has a profound impact on the prevention of diet-induced metabolic syndrome parameters, non-alcoholic fatty liver disease (NAFLD) progression, and renal dysfunction. Despite enhanced caloric intake, NLRX1 deletion in mice fed a western diet (WD) results in protection from liver steatosis, hepatic fibrosis, obesity, insulin resistance, glycosuria and kidney dysfunction parameters independent from inflammation. While mitochondrial content was equal, NLRX1 loss in hepatocytes leads to increased fatty acid oxidation and decreased steatosis. In contrast, glycolysis was decreased in NLRX1-deficient cells versus controls. Thus, although first implicated in immune regulation, we show that NLRX1 function extends to the control of hepatocyte energy metabolism via the restriction of mitochondrial fatty acid-dependent OXPHOS and enhancement of glycolysis. As such NLRX1 may be an attractive novel therapeutic target for NAFLD and metabolic syndrome.

Keywords: Fatty acid oxidation; Innate immune receptor NLRX1; Kidney disease; Metabolic syndrome; Metabolism; NAFLD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dietary Fats / adverse effects*
  • Dietary Fats / pharmacology
  • Fatty Acids / genetics
  • Fatty Acids / metabolism*
  • Fatty Liver / chemically induced
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Gene Deletion
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Metabolic Syndrome / chemically induced
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism*
  • Metabolic Syndrome / pathology
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver / genetics
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology
  • Mitochondrial Proteins / deficiency*


  • Dietary Fats
  • Fatty Acids
  • Mitochondrial Proteins
  • NLRX1 protein, mouse