Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis.
In the early stages of nonalcoholic fatty liver disease (NAFLD), triglycerides accumulate in hepatocytes. Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in hepatocyte triglyceride biosynthesis. DGAT2 antisense oligonucleotide (ASO) treatment improved hepatic steatosis dramatically in a previous study of obese mice. According to the 2-hit hypothesis for progression of NAFLD, hepatic steatosis is a risk factor for nonalcoholic steatohepatitis (NASH) and fibrosis. To evaluate this hypothesis, we inhibited DGAT2 in a mouse model of NASH induced by a diet deficient in methionine and choline (MCD). Six-week-old genetically obese and diabetic male db/db mice were fed either the control or the MCD diet for 4 or 8 weeks. The MCD diet group was treated with either 25 mg/kg DGAT2 ASO or saline intraperitoneally twice weekly. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress, and systemic insulin sensitivity were evaluated. Hepatic steatosis, necroinflammation, and fibrosis were increased in saline-treated MCD diet-fed mice compared to controls. Treating MCD diet-fed mice with DGAT2 ASO for 4 and 8 weeks decreased hepatic steatosis, but increased hepatic free fatty acids, cytochrome P4502E1, markers of lipid peroxidation/oxidant stress, lobular necroinflammation, and fibrosis. Progression of liver damage occurred despite reduced hepatic expression of tumor necrosis factor alpha, increased serum adiponectin, and striking improvement in systemic insulin sensitivity.


CONCLUSIONS
Results from this mouse model would suggest accumulation of triglycerides may be a protective mechanism to prevent progressive liver damage in NAFLD.
Yamaguchi
Kanji
K
Division of Gastroenterology, Duke University Medical Center, 595 LaSalle Street, Durham, NC 27710, USA.
Yang
Liu
L
McCall
Shannon
S
Huang
Jiawen
J
Yu
Xing Xian
XX
Pandey
Sanjay K
SK
Bhanot
Sanjay
S
Monia
Brett P
BP
Li
Yin-Xiong
YX
Diehl
Anna Mae
AM
D052242:Adiponectin / Q000097:blood; D000821:Animal Feed; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002794:Choline / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000097:blood; D015227:Lipid Peroxidation / Q000502:physiology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D014280:Triglycerides / Q000096:biosynthesis* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052242:Adiponectin; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020320:Oligoribonucleotides, Antisense; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D008715:Methionine; D019392:Cytochrome P-450 CYP2E1; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D002794:Choline