Hepatocyte and stellate cell deletion of liver fatty acid binding protein reveals distinct roles in fibrogenic injury

Abstract

Liver fatty acid binding protein (L‐Fabp) modulates lipid trafficking in enterocytes, hepatocytes, and hepatic stellate cells (HSCs). We examined hepatocyte vs. HSC L‐Fabp deletion in hepatic metabolic adaptation and fibrotic injury. Floxed L‐Fabp mice were bred to different transgenic Cre mice or injected with adeno‐associated virus type 8 (AAV8) Cre and fed diets to promote steatosis and fibrosis or were subjected to either bile duct ligation or CCl4 injury. Albumin‐Cre‐mediated L‐Fabp deletion revealed recombination in hepatocytes and HSCs; these findings were confirmed with 2 other floxed alleles. Glial fibrillary acid protein‐Cre and platelet‐derived growth factor receptor β‐Cre‐mediated L‐Fabp deletion demonstrated recombination only in HSCs. Mice with albumin promoter‐driven Cre recombinase (Alb‐Cre)‐mediated or AAV8‐mediated L‐Fabp deletion were protected against food withdrawal‐induced steatosis. Mice with Alb‐Cre‐mediated L‐Fabp deletion were protected against high saturated fat‐induced steatosis and fibrosis, phenocopying germline L‐Fabp−/− mice. Mice with HSC‐specific L‐Fabp deletion exhibited retinyl ester depletion yet demonstrated no alterations in fibrosis. On the other hand, fibrogenic resolution after CCl4 administration was impaired in mice with Alb‐Cre‐mediated L‐Fabp deletion. These findings suggest cell type‐specific roles for L‐Fabp in mitigating hepatic steatosis and in modulating fibrogenic injury and reversal.—Newberry, E. P., Xie, Y., Lodeiro, C., Solis, R., Moritz, W., Kennedy, S., Barron, L., Onufer, E., Alpini, G., Zhou, T., Blaner, W. S., Chen, A., Davidson, N. O. Hepatocyte and stellate cell deletion of liver fatty acid binding protein reveal distinct roles in fibrogenic injury. FASEB J. 33, 4610–4625 (2019). http://www.fasebj.org

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“…A). As reported recently, Albumin‐Cre also leads to a Cre‐mediated recombination in both hepatocytes and HSCs . To verify this in our transgenic mice, we isolated primary hepatocytes, HSCs, and Kupffer cells from WT and Tg mice.…”

“…As reported recently, Albumin-Cre also leads to a Cre-mediated recombination in both hepatocytes and HSCs. (18) To verify this in our transgenic mice, we isolated primary hepatocytes, HSCs, and Kupffer cells from WT and Tg mice. Indeed, Sesn3 transgene was expressed in both hepatocytes and HSCs but not Kupffer cells after the Albumin-Cre-mediated recombination (Supporting Fig.…”

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“…23 Mice with albumin promoter-driven Cre recombinase (Alb-Cre mice) have Cre expression selectively in hepatocytes and hepatic stellate cells (HSCs). 24 Zhang et al generated Alb-Cre-mediated liver-specific BMAL1 knockout mice and found that these mice had higher serum aminotransferase (ALT) levels and liver steatosis compared to control mice after chronic and binge alcohol feeding. 25 Hepatic BMAL1 deficiency decreased expression levels of genes associated with de novo lipogenesis and β-oxidation in the liver, indicating the association between clock genes and liver steatosis.…”

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“…Studies have shown that the loss of L-FABP may enhance the production of lipotoxic inflammatory mediators, impair the oxidative pathway of FAs, and render hepatocytes more vulnerable to the harmful effects of LCFAs, thus promoting the development of NAFLD (62,63). Consistent with these studies, the expression of L-FABP and CPT1α was significantly reduced in HFD-fed hamsters, which suggested that delivery of FAs to mitochondria was inhibited, thereby impairing oxidation and leading to overaccumulation of FAs.…”