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Abstract: Objective To investigate the angiogenesis inhibitor ZM 306316 in regulating visceral
fat function and analyze the protective effect on non-alcoholic fatty liver disease (NAFLD)
induced by high-fat diet in mice and its possible mechanism. Methods Total of thirty-two
C57BL / 6J mice were randomly divided into high fat diet group (130 kcal l% fat diet, 11 cases,
HFD group), low fat diet group (45 kcal l% fat diet, 11 cases, LFD group) and high fat dietZM group (0.8% ZM 306416 was added, 10 cases, HFD-ZM group), the mice were fed on
different diets for 15 weeks. The body weight of the mice were measured regularly. The serum
biochemistry index of the mice were detected, including alanine aminotransferase (ALT),
aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG) and free fatty acids
(FFA). The number of vascular pseudophlebrand factor (von Willebrand factor, vWF) positive
cells in epididymal adipose tissue was analyzed by immunohistochemistry. Real-time ?uorescent
quantitative polymerase chain reaction (FQ-PCR) was used to detect the expression of relevant
genes in each tissue. Results The body mass [(37.53 ± 3.64) g vs (45.17 ± 3.22) g], VAT mass
[(2.25 ± 0.85) g vs (3.34 ± 0.54) g], visceral adipocyte size [(7854.9 ± 60.4) mm2 vs (10800.6 ±
52.7) mm2], vWF positive cells (47.32 ± 6.2 vs 31.2 ± 5.4), vascular density [(320.47 ± 10.66)%
vs (184.26 ± 14.94)%] and angiogenic factor VEGF-A mRNA relative expression (0.54 ± 0.16 vs
0.24 ± 0.12) of mice in HFD-ZM group were signifcantly lower than those in HFD group, and
the relative mRNA expression of the anti-angiogenic factor TSP-1 was signifcantly higher (0.32 ± 0.07
vs 0.42 ± 0.14), the differences were statistically signifcant (all P ＜ 0.05). The level of ALT
[(122.47 ± 4.11) U/L vs (95.28 ± 2.21) U/L], AST [(172.17 ± 5.20) U/L vs (124.39 ± 2.54) U/L],
TG [(4.91 ± 1.13) mmol/L vs (3.56 ± 1.07) mmol/L], FFA [(1640.55 ± 22.51) μEq/L
vs (1131.62 ± 18.33) μEq/L] and TC [(8.10 ± 2.11) mmol/L vs (6.11 ± 2.19) mmol/L]
of mice in HFD-ZM group were signifcantly lower than those in HFP group, the differences
were statistically significant (all P ＜ 0.05). A small amount of collagen fibroplasia was
seen in the liver lobe and portal canal, mainly around the central vein, with a significant
decrease in the number of α -SMA positive cells. Compared with those in HFD group,
the relative mRNA expression of fatty acid oxidation genes (CPT-1: 1.64 ± 0.17 vs 0.97 ±
0.24; MCAD: 1.23 ± 0.18 vs 0.91 ± 0.16) of mice in HFD-ZM group increased signifcantly (all
P ＜ 0.05), the relative mRNA expression of adipogenesis gene (PPARγ: 0.63 ± 0.24 vs 1.03 ±
0.27) decreased significantly (P ＜ 0.05), the relative mRNA expression of cholesterol
generation related genes (FXR: 0.76 ± 0.03 vs 0.65 ± 0.10; HMGCR: 1.04 ± 0.14 vs 0.89 ± 0.17)
increased signifcantly (all P ＜ 0.05), the relative mRNA expression of in?ammation-related
genes (TNF-α: 0.57 ± 0.13 vs 1.01 ± 0.23; CD68: 1.02 ± 0.19 vs 1.62 ± 0.09; MCP-1: 0.59 ±
0.11 vs 1.01 ± 0.09; MARCO: 0.54 ± 0.13 vs 1.02 ± 0.12; ICAM-1: 0.94 ± 0.20 vs 1.56 ± 0.13;
VCAM-1: 1.12 ± 0.23 vs 1.89 ± 0.16) and liver fbrosis-related genes (TGFβ: 0.64 ± 0.16 vs
1.02 ± 0.19; α-SMA: 0.66 ± 0.11 vs 1.03 ± 0.06) decreased signifcantly (all P ＜ 0.05), the
relative mRNA expression of antioxidant genes (SOD2: 0.83 ± 0.12 vs 0.71 ± 0.13) and
apoptotic genes (Bcl-2: 0.78 ± 0.12 vs 0.58 ± 0.03) increased significantly (all P ＜ 0.05).
Conclusions ZM 306416, an angiogenesis inhibitor, can improve visceral adipose tissue
function and lipid metabolism by regulating adipogenesis and liver steatosis, and can inhibit
NAFLD induced by high-fat diet in mice.
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