Hepatic DGAT1 deficiency protects against hepatic steatosis induced by high-fat diet. (A) RT-PCR analysis of Dgat1 and Dgat2 mRNA in liver and epidydimal white adipose tissue (WAT). Male Dgat1^flox/flox mice received adenoviruses expressing LacZ or Cre recombinase. After 4 weeks, mice were fed a high-fat diet for 3 weeks (age 16–20 weeks, n=5–6/genotype). * P<0.001 vs. control. (B) Microsomal hepatic DGAT activity as measured by the incorporation of [¹⁴C]-oleoyl-CoA into triglycerides (age 16–20 weeks, n=5–6/genotype). P * <0.001 vs. control. (C and D) Livers (C) and hepatic triglyceride content (D) in mice fed high-fat diet (age 16–20 weeks, n=5–6 per genotype). P * <0.05 vs. control.

DGAT1 deficiency does not protect against hepatic steatosis due to lipodystrophy or liver receptor X (LXR) activation. (A) Real-time PCR analysis of sterol regulatory element-binding protein (Srebp1c), fatty acid (FA) synthase (fasn), and stearoyl-CoA desaturase 1 (scd1) and Dgat2 mRNA levels in livers of male mice (age 24 weeks, n=5–7/genotype). P * <0.001, **P<0.05 vs. Dgat1^+/+. (B) Hepatic triglyceride content in chow-fed male mice (age 24 weeks, n=7/genotype). P * <0.001 vs. Dgat1^+/+ and Dgat1^−/− mice. (C) Livers and Oil-Oed-O (ORO)-stained liver sections in 24-week-old male mice. (D) Real-time PCR analysis of FA synthase (Fasn) and stearoyl-CoA desaturase 1 (Scd1) mRNA levels in livers of mice treated with LXR agonist (T0901317, 50 mg/kg; n=5). P * <0.001 vs. Dgat1^+/+ and Dgat1^−/− mice. (E) Hepatic triglyceride content in male mice treate with 50-mg/kg T0901317 (n=5). P * <0.001 vs. Dgat1^+/+ and Dgat1^−/− mice.

Protection against hepatic steatosis in Dgat1^−/− mice fed a high-fat diet. (A) Livers and Oil-Red-O (ORO)-stained liver sections in 12-week-old mice fed a high-fat diet for 3 weeks. (B) Fatty acid (FA) composition of hepatic TG in mice fed a chow or high-fat diet (age 8–12 weeks, n=5/genotype). SFA, saturated FAs; MUFA, monounsaturated FAs; PUFA, polyunsaturated FAs. P * <0.001 vs. control. (C) FA synthesis in hepatocytes from mice fed chow or high-fat diet. P * <0.05 vs. chow-fed mice. * P<0.001 vs. high-fat control. (D) mRNA levels of sterol regulatory element-binding protein 1c (Srebp1c), FA synthase (fasn), stearoyl-CoA desaturase 1 (scd1), carbohydrate response element binding protein (Chrebp), and liver-pyruvate kinase (L-pk) in livers of mice fed chow or high-fat diet. Genes were normalized to cyclophilin or 36B4 (age 8–12 weeks, n=5). *P<0.05 vs. control. (E) Rate of FA oxidation in hepatocytes from Dgat1^+/+ or Dgat1^−/− mice fed chow or high-fat diet (age 12–16 weeks, n=2–3/genotype). P * <0.001 vs. control. (F) mRNA levels of peroxisome proliferators-activated receptor α (Pparα), carnitine palmitoyl-transferase 1 (Cpt1), and acyl-CoA oxidase (Aox) in livers from fat-fed Dgat1^+/+ or Dgat1^−/− mice (age 8–12 weeks, n=5).

Protection against fasting-induced hepatic steatosis in DGAT1-deficient and Liv-D1KO mice. (A) Real-time PCR analysis of Dgat1 and Dgat2 mRNA levels in livers of male mice fed ad libitum (Ad Lib), fasted for 16 h (Fast), or fasted for 24 h and refed for 12 h (Refed) (age 13–14 weeks, n=6–8/group). *P<0.001 vs. control. (B and C) Gross appearance of livers (B), and hepatic triglyceride content (C) after 20 hours of fasting (age 12 weeks, n=5/genotype). *P<0.001 vs. control. (D) Real-time PCR analysis of Dgat1, Dgat2, peroxisome proliferator-activated receptor alpha (Ppara), and target genes, carnitine-palmitoyl transferase 1(Cpt1), aldehyde dehydrogenase 3 family member A2 (Aldh3a2), enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase (Ehhadh), and cytochrome P450, family 4, subfamily a, polypeptide 10 (Cypa10) mRNA levels in liver and gastrocnemius of 20 hour fasted mice. (age 16–20 weeks, n=4–5/genotype). *P<0.002 vs. control. (E) Microsomal hepatic DGAT activity measured by incorporation of [¹⁴C]-oleoyl-CoA into triglycerides (age 16–20 weeks, n=4/genotype). *P<0.001 vs. control. (F and G) Livers (F) and hepatic triglyceride content (G) in mice fasted for 20 h. (age 16–20 weeks, n=5/group). *P<0.01 vs. control. The experiment was repeated with similar results. (H) Triglyceride synthesis in hepatocytes challenged with palmitate (16:0) conjugated to bovine serum albumin as measured by incorporation of [¹⁴C]-Glycerol into triglycerides. The experiment was repeated with similar results.

Pharmacologic inhibition of Dgat1 mRNA prevents hepatic steatosis in mice fed a high-fat diet. (A) Real-time PCR analysis of Dgat1 and Dgat2 mRNA after treatment with control or Dgat1 anisense oligonucleotides (ASO), administered twice weekly (50 mg/kg intraperitoneally). *P<0.01 vs. control. (B) Hepatic triglyceride content after 1 week of high-fat diet after pretreatment with control or Dgat1 ASO (n=5). *P<0.05 vs. control.