TY - JOUR
T1 - Sex and BNIP3 genotype, rather than acute lipid injection, modulate hepatic mitochondrial function and steatosis risk in mice
AU - Fuller, Kelly N.Z.
AU - McCoin, Colin S.
AU - Allen, Julie
AU - Bell-Glenn, Shelby
AU - Koestler, Devin C.
AU - Dorn, Gerald W.
AU - Thyfault, John P.
N1 - Publisher Copyright:
© 2020 American Physiological Society. All rights reserved
PY - 2020/5
Y1 - 2020/5
N2 - Both lipid oversupply and poor mitochondrial function (low respiration and elevated H2O2 emission) have been implicated in the development of hepatic steatosis and liver injury. Mitophagy, the targeted degradation of low-functioning mitochondria, is critical for maintaining mitochondrial quality control. Here, we used intralipid injection combined with acute (4 day) and chronic (4-7wk) high-fat diets (HFD) to examine whether hepatic mitochondrial respiration would decrease and H2O2 emission would increase with lipid overload. We tested these effects in male and female wild type (WT) mice and mice null for a critical mediator of mitophagy, BCL-2/adenovirus EIB 19-kDa interacting protein knockout (BNIP3 KO) housed at thermoneutral temperatures. Intralipid injection was successful in elevating serum triglycerides and nonesterified fatty acids but had no impact on hepatic mitochondrial respiratory function or H2O2 emission. However, female mice had greater mitochondrial respiration on the acute HFD and lower H2O2 emission across both HFD durations and were protected against hepatic steatosis. Unexpectedly, BNIP3 KO animals had greater hepatic mitochondrial respiration, better coupled respiration, and increased electron chain protein content after the 4-day HFD, compared with WT animals. Altogether, these data suggest that acute lipid overload delivered by a single intralipid bolus does not alter hepatic mitochondrial outcomes, but rather sex and genotype profoundly impact hepatic mitochondrial respiration and H2O2 emission.
AB - Both lipid oversupply and poor mitochondrial function (low respiration and elevated H2O2 emission) have been implicated in the development of hepatic steatosis and liver injury. Mitophagy, the targeted degradation of low-functioning mitochondria, is critical for maintaining mitochondrial quality control. Here, we used intralipid injection combined with acute (4 day) and chronic (4-7wk) high-fat diets (HFD) to examine whether hepatic mitochondrial respiration would decrease and H2O2 emission would increase with lipid overload. We tested these effects in male and female wild type (WT) mice and mice null for a critical mediator of mitophagy, BCL-2/adenovirus EIB 19-kDa interacting protein knockout (BNIP3 KO) housed at thermoneutral temperatures. Intralipid injection was successful in elevating serum triglycerides and nonesterified fatty acids but had no impact on hepatic mitochondrial respiratory function or H2O2 emission. However, female mice had greater mitochondrial respiration on the acute HFD and lower H2O2 emission across both HFD durations and were protected against hepatic steatosis. Unexpectedly, BNIP3 KO animals had greater hepatic mitochondrial respiration, better coupled respiration, and increased electron chain protein content after the 4-day HFD, compared with WT animals. Altogether, these data suggest that acute lipid overload delivered by a single intralipid bolus does not alter hepatic mitochondrial outcomes, but rather sex and genotype profoundly impact hepatic mitochondrial respiration and H2O2 emission.
KW - Liver
KW - Metabolism
KW - NAFLD
KW - Reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85084636522&partnerID=8YFLogxK
U2 - 10.1152/japplphysiol.00035.2020
DO - 10.1152/japplphysiol.00035.2020
M3 - Article
C2 - 32240015
AN - SCOPUS:85084636522
SN - 8750-7587
VL - 128
SP - 1251
EP - 1261
JO - Journal of Applied Physiology
JF - Journal of Applied Physiology
IS - 5
ER -