Hepatocyte-specific TM6SF2 knockout aggravates hepatic steatosis in mice with nonalcoholic fatty liver disease

Jie ZHANG; Xuefeng MA; Yifen WANG; Mengke WANG; Likun ZHUANG; Shousheng LIU; Yongning XIN

doi:10.3969/j.issn.1001-5256.2021.11.024

Volume 37 Issue 11

Nov. 2021

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Article Navigation > Journal of Clinical Hepatology > 2021 > 37(11): 2612-2616

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Hepatocyte-specific TM6SF2 knockout aggravates hepatic steatosis in mice with nonalcoholic fatty liver disease

DOI: 10.3969/j.issn.1001-5256.2021.11.024

1.
Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266011, China
2.
Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266071, China
3.
Qingdao Key Laboratory of Digestive Diseases, Qingdao, Shandong 266071, China

Research funding:

National Natural Science Foundation of China (31770837)

Received Date: 2021-04-26
Accepted Date: 2021-06-04
Published Date: 2021-11-20

Abstract

Abstract

Objective To establish a mouse model of hepatocyte-specific TM6SF2 knockout, and to investigate the role of TM6SF2 in the development of nonalcoholic fatty liver disease (NAFLD). Methods The CRISPR/Cas9 technique and the Cre/LoxP strategy were used to establish a stable mouse model of hepatocyte-specific TM6SF2 knockout. The mice with hepatocyte-specific TM6SF2 knockout and the control mice were given a normal diet or a high-fat diet (HFD) for 16 weeks, and related indices were measured, including general status (body weight and liver weight), glucose metabolic indices (fasting blood glucose and insulin), and lipid metabolism (plasma triglyceride, cholesterol, and liver triglyceride). The t-test was used for comparison of normally distributed continuous data between two groups. Results Under the condition of HFD, compared with the control mice, the mice with hepatocyte-specific TM6SF2 knockout had significantly higher liver weight (2.235±0.175 g vs 1.258±0.106 g, t=4.789, P < 0.01) and liver index (4.970%±0.298% vs 3.210%±0.094%, t=5.630, P < 0.01), and the loss of the TM6SF2 gene in hepatocytes aggravated the abnormal level of alanine aminotransferase induced by HFD (62.517±1.526 U/L vs 25.991±5.947 U/L, t=5.949, P < 0.01). Compared with the control mice under the condition of normal diet or HFD, the mice with TM6SF2 knockout had a significant increase in plasma insulin level (normal diet: 37.203±0.836 mIU/L vs 34.835±0.426 mIU/L, t=2.520, P=0.025; HFD: 41.093±1.226 mIU/L vs 35.817±0.500 mIU/L, t=3.985, P=0.007), while there were no significant differences in the other indices associated with glucose metabolism (all P > 0.05). Under the condition of HFD, there were no significant differences in the levels of plasma triglyceride and cholesterol between the mice with hepatocyte-specific TM6SF2 knockout and the control group (P > 0.05), while the mice with hepatocyte-specific TM6SF2 knockout had a significant increase in the level of liver triglyceride compared with the control mice (23.969±0.978 mg/g vs 18.229±1.633 mg/g, t=3.015, P=0.024). Conclusion Hepatocyte-specific knockout of TM6SF2 can aggravate liver lipid accumulation and liver injury in mice with NAFLD.
- Non-alcoholic Fatty Liver Disease,
- TM6SF2,
- CRISPR/Cas9

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References

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Hepatocyte-specific TM6SF2 knockout aggravates hepatic steatosis in mice with nonalcoholic fatty liver disease

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Hepatocyte-specific TM6SF2 knockout aggravates hepatic steatosis in mice with nonalcoholic fatty liver disease

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