Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models.

UNLABELLED: Liver regeneration is impaired following partial hepatectomy (PH) in mice with genetic obesity and hepatic steatosis and also in wild-type mice fed a high-fat diet. These findings contrast with other data showing that liver regeneration is impaired in mice in which hepatic lipid accumulation is suppressed by either pharmacologic leptin administration or by disrupted glucocorticoid signaling. These latter findings suggest that hepatic steatosis may actually be required for normal liver regeneration. We have reexamined this relationship using several murine models of altered hepatic lipid metabolism. Liver fatty acid (FA) binding protein knockout mice manifested reduced hepatic triglyceride (TG) content compared to controls, with no effect on liver regeneration or hepatocyte proliferation. Examination of early adipogenic messenger RNAs revealed comparable induction in liver from both genotypes despite reduced hepatic steatosis. Following PH, hepatic TG was reduced in intestine-specific microsomal TG transfer protein deleter mice, which fail to absorb dietary fat, increased in peroxisome proliferator activated receptor alpha knockout mice, which exhibit defective FA oxidation, and unchanged (from wild-type mice) in liver-specific FA synthase knockout mice in which endogenous hepatic FA synthesis is impaired. Hepatic TG increased in the regenerating liver in all models, even in animals in which lipid accumulation is genetically constrained. However, in no model -- and over a >90-fold range of hepatic TG content -- was liver regeneration significantly impaired following PH. CONCLUSION: Although hepatic TG content is widely variable and increases during liver regeneration, alterations in neither exogenous or endogenous lipid metabolic pathways, demonstrated to promote or diminish hepatic steatosis, influence hepatocyte proliferation.

Inhibition of ADRP prevents diet-induced insulin resistance.

Diets with high fat content induce steatosis, insulin resistance, and type 2 diabetes. The lipid droplet protein adipose differentiation-related protein (ADRP) mediates hepatic steatosis, but whether this affects insulin action in the liver or peripheral organs in diet-induced obesity is uncertain. We fed C57BL/6J mice a high-fat diet and simultaneously treated them with an antisense oligonucleotide (ASO) against ADRP for 4 wk. Glucose homeostasis was assessed with clamp and tracer techniques. ADRP ASO decreased the levels of triglycerides and diacylglycerol in the liver, but fatty acids, long-chain fatty acyl CoAs, ceramides, and cholesterol were unchanged. Insulin action in the liver was enhanced after ADRP ASO treatment, whereas muscle and adipose tissue were not affected. ADRP ASO increased the phosphorylation of insulin receptor substrate (IRS)1, IRS2, and Akt, and decreased gluconeogenic enzymes and PKCepsilon, consistent with its insulin-sensitizing action. These results demonstrate an important role for ADRP in the pathogenesis of diet-induced insulin resistance.