This study examined whether enhanced susceptibility of steatotic liver to I/R injury is due to impaired recruitment of bone marrow (BM) progenitors of LSECs (also called sprocs) with diminished repair of injured LSECs and whether restoring signaling to recruit BM sprocs reduces I/R injury.
Hepatic vessels were clamped for 1 hour in rats fed a high fat, high fructose (HFHF) diet for 5, 10, or 15 weeks. MMP-9 antisense oligonucleotides (ASO) or an MMP inhibitor were used to induce liver-selective MMP-9 inhibition.
HFHF rats had mild, moderate and severe steatosis, respectively, at 5-, 10-, and 15-weeks. I/R injury was enhanced in HFHF rats; this was accompanied by complete absence of hepatic VEGF-sdf1 signaling, leading to lack of BM sproc recruitment. Liver-selective MMP-9 inhibition to protect against proteolytic cleavage of hepatic VEGF using either MMP-9 ASO or intraportal MMP inhibitor in 5- and 10-week HFHF rats enhanced hepatic VEGF-sdf1 signaling, increased BM sproc recruitment, and reduced ALT by 92 and 77% at 5 weeks and by 80 and 64% at 10-weeks of HFHF diet, respectively. After I/R injury in 15-week HFHF rats, the MMP inhibitor reduced active MMP-9 expression by 97%, ameliorated histologic evidence of injury, and reduced ALT by 58%, which is comparable to control rats sustaining I/R injury. Rescue therapy with intraportal MMP inhibitor, given after ischemia, in the 5-week HFHF rat reduced ALT by 71% and reduced necrosis.
Lack of signaling to recruit BM sprocs that repair injured LSECs renders steatotic liver more susceptible to I/R injury. Liver-selective MMP-9 inhibition enhances VEGF-sdf1 signaling and recruitment of BM sprocs, which markedly protects against I/R injury, even in severely steatotic rats.

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