TY - JOUR
T1 - Hepatocyte- or macrophage-specific SREBP-1a deficiency in mice exacerbates methionine- and choline-deficient diet-induced nonalcoholic fatty liver disease
AU - Araki, Masaya
AU - Nakagawa, Yoshimi
AU - Saito, Hodaka
AU - Yamada, Yasunari
AU - Han, Song Iee
AU - Mizunoe, Yuhei
AU - Ohno, Hiroshi
AU - Miyamoto, Takafumi
AU - Sekiya, Motohiro
AU - Matsuzaka, Takashi
AU - Sone, Hirohito
AU - Shimano, Hitoshi
N1 - Publisher Copyright:
© 2022 American Physiological Society. All rights reserved.
PY - 2022/12
Y1 - 2022/12
N2 - Sterol regulatory element-binding proteins (SREBPs) are master transcription factors for lipid synthesis, and SREBP-1 is important for fatty acid and triglyceride synthesis. SREBP-1 has two isoforms, SREBP-1a and SREBP-1c, which are splicing variants transcribed from the Srebf1 gene. Although SREBP-1a exhibits stronger transcriptional activity than SREBP-1c, hepatic SREBP-1c is considered more physiologically important. We generated SREBP-1a flox mice using the CRISPR/Cas9 system and hepatocyte- and macrophage-specific SREBP-1a knockout (KO) mice (LKO, liver-knockout; and mUKO, macrophage-knockout). There were no significant differences among all the mouse genotypes upon feeding with a normal diet. However, feeding with a methionine- and choline-deficient (MCD) diet resulted in exacerbated liver injury in both KO mice. In LKO mice, fatty liver was unexpectedly exacerbated, leading to macrophage infiltration and inflammation. In contrast, in mUKO mice, the fatty liver state was similar to that in flox mice, but the polarity of the macrophages in the liver was transformed into a proinflammatory M1 subtype, resulting in the exacerbation of inflammation. Taken together, we found that SREBP-1a does not contribute to hepatic lipogenesis, but in either hepatocytes or macrophages distinctly controls the onset of pathological conditions in MCD diet-induced hepatitis.
AB - Sterol regulatory element-binding proteins (SREBPs) are master transcription factors for lipid synthesis, and SREBP-1 is important for fatty acid and triglyceride synthesis. SREBP-1 has two isoforms, SREBP-1a and SREBP-1c, which are splicing variants transcribed from the Srebf1 gene. Although SREBP-1a exhibits stronger transcriptional activity than SREBP-1c, hepatic SREBP-1c is considered more physiologically important. We generated SREBP-1a flox mice using the CRISPR/Cas9 system and hepatocyte- and macrophage-specific SREBP-1a knockout (KO) mice (LKO, liver-knockout; and mUKO, macrophage-knockout). There were no significant differences among all the mouse genotypes upon feeding with a normal diet. However, feeding with a methionine- and choline-deficient (MCD) diet resulted in exacerbated liver injury in both KO mice. In LKO mice, fatty liver was unexpectedly exacerbated, leading to macrophage infiltration and inflammation. In contrast, in mUKO mice, the fatty liver state was similar to that in flox mice, but the polarity of the macrophages in the liver was transformed into a proinflammatory M1 subtype, resulting in the exacerbation of inflammation. Taken together, we found that SREBP-1a does not contribute to hepatic lipogenesis, but in either hepatocytes or macrophages distinctly controls the onset of pathological conditions in MCD diet-induced hepatitis.
KW - SREBP-1a
KW - inflammation
KW - liver injury
KW - tissue-specific SREBP-1a knockout mice
UR - http://www.scopus.com/inward/record.url?scp=85143088707&partnerID=8YFLogxK
U2 - 10.1152/ajpgi.00090.2022
DO - 10.1152/ajpgi.00090.2022
M3 - 学術論文
C2 - 36283088
AN - SCOPUS:85143088707
SN - 0193-1857
VL - 323
SP - G627-G639
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 6
ER -