The role of small heterodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice.
OBJECTIVE
Bile acids (BA) are elevated after vertical sleeve gastrectomy (VSG) and farnesoid-X-receptor (FXR) is critical to the success of murine VSG. BA downregulate hepatic lipogenesis by activating the FXR-small heterodimer partner (SHP) pathway. The role of SHP in fatty liver disease improvement after VSG was tested.


METHODS
Wild type (WT), SHP liver transgenic (SHP-Tg), and SHP knockout (SHP-KO) high-fat diet (HFD) fed mice underwent either VSG or Sham surgery. Body weight, BA level and composition, steatosis, and BA metabolism gene expression were evaluated.


RESULTS
Obese WT mice post-VSG lost weight, reduced steatosis, decreased plasma alanine aminotransferase (ALT), had more BA absorptive ileal area, and elevated serum BA. Obese SHP-Tg mice post-VSG also lost weight and had decreased steatosis. SHP-KO mice were however resistant to steatosis despite weight gain on a HFD. Further SHP-KO mice that underwent VSG lost weight, but developed hepatic inflammation and had increased ALT.


CONCLUSIONS
VSG produces weight loss independent of SHP status. SHP ablation creates a proinflammatory phenotype which is exacerbated after VSG despite weight loss. These inflammatory alterations are possibly related to factors extrinsic to a direct manifestation of NASH.
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Andriy
A
Myronovych
Rosa-Maria
RM
Salazar-Gonzalez
Karen K
KK
Ryan
Lili
L
Miles
Wujuan
W
Zhang
Pinky
P
Jha
Li
L
Wang
Kenneth D R
KD
Setchell
Randy J
RJ
Seeley
Rohit
R
Kohli
D000818:Animals; D059305:Diet, High-Fat; D005743:Gastrectomy; D007249:Inflammation / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000235:genetics / Q000601:surgery*; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D015430:Weight Gain / Q000235:genetics; D015431:Weight Loss / Q000235:genetics
D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2