Acetyl‐CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents

Abstract

Pharmacologic inhibition of acetyl-CoA carboxylase (ACC) enzymes, ACC1 and ACC2, offers an attractive therapeutic strategy for nonalcoholic fatty liver disease (NAFLD) through simultaneous inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. However, the effects of ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo are unknown. Here, we evaluated the effect of a liver-directed allosteric inhibitor of ACC1 and ACC2 (Compound 1) on these parameters, as well as glucose and lipid metabolism, in control and diet-induced rodent models of NAFLD. Oral administration of Compound 1 preferentially inhibited ACC enzymatic activity in the liver, reduced hepatic malonyl-CoA levels, and enhanced hepatic ketogenesis by 50%. Furthermore, administration for 6 days to high-fructose-fed rats resulted in a 20% reduction in hepatic de novo lipogenesis. Importantly, long-term treatment (21 days) significantly reduced high-fat sucrose diet-induced hepatic steatosis, protein kinase C epsilon activation, and hepatic insulin resistance. ACCi treatment was associated with a significant increase in plasma triglycerides (approximately 30% to 130%, depending on the length of fasting). ACCi-mediated hypertriglyceridemia could be attributed to approximately a 15% increase in hepatic very low-density lipoprotein production and approximately a 20% reduction in triglyceride clearance by lipoprotein lipase (P ≤ 0.05). At the molecular level, these changes were associated with increases in liver X receptor/sterol response element-binding protein-1 and decreases in peroxisome proliferator-activated receptor-α target activation and could be reversed with fenofibrate co-treatment in a high-fat diet mouse model. Conclusion: Collectively, these studies warrant further investigation into the therapeutic utility of liver-directed ACC inhibition for the treatment of NAFLD and hepatic insulin resistance.

Fructose and metabolic health: governed by hepatic glycogen status?

“…), and pharmacological inhibition of ACC can decrease hepatic DNL and hepatic steatosis (Goedeke et al . ). This is, however, at the expense of hypertriglyceridaemia (Goedeke et al .…”

“…This is, however, at the expense of hypertriglyceridaemia (Goedeke et al . ). In human‐derived HEPG2 cells, addition of fructose to glucose does not further upregulate ACC expression (Hirahatake et al .…”

Trimming the Fat: Acetyl‐CoA Carboxylase Inhibition for the Management of NAFLD

“…These findings have now been validated in a phase II trial of a liver-targeted, allosteric inhibitor of ACC1 and ACC2, which demonstrated reduced hepatic steatosis and improved markers of fibrosis. (5) Hypertriglyceridemia, an unanticipated response to long-term ACC inhibition, has been observed in both rodents (4,6) and humans. (5,6) Goedeke et al (4) as well as Kim et al (6) have now shed light on this phenomenon as a previously unappreciated mechanistic point of control in triglyceride metabolism.…”

“…Liver-directed inhibition of ACC1 and ACC2 reduces de novo lipogenesis and increases fatty acid β-oxidation. (4,6) Despite reductions in triglycerides content in the liver and improvements in insulin sensitivity, liver-directed inhibition of ACC1 and ACC2 leads to a decrease in polyunsaturated fatty acids and an increase in SREBP1c, GPAT1 expression and VLDL secretion, eventually leading to hypertriglyceridemia. Fibrate drugs decrease plasma triglycerides by enhancing fatty acid oxidation in the liver and by promoting lipoprotein lipase-mediated triglyceride clearance from the plasma.…”

“…Small molecule inhibitors have been identified and tested in rodents and humans. These efforts, including by Goedeke et al, have yielded both promising and unexpected results. ACC inhibitors decrease hepatic triglyceride contents, which is attributable to anticipated effects of reducing de novo lipogenesis and increasing rates of fatty acid oxidation.…”