Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver

Abstract

Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and may result primarily from increased hepatic de novo lipogenesis (PRIM) or secondarily from adipose tissue lipolysis (SEC). We studied mice with hepatocyte- or adipocyte-specific SREBP-1c overexpression as models of PRIM and SEC. PRIM mice featured increased lipogenic gene expression in the liver and adipose tissue. Their selective, liver-specific insulin resistance was associated with increased C18:1-diacylglycerol content and protein kinase Cε translocation. SEC mice had decreased lipogenesis mediated by hepatic cholesterol responsive element–binding protein and featured portal/lobular inflammation along with total, whole-body insulin resistance. Hepatic mitochondrial respiration transiently increased and declined with aging along with higher muscle reactive oxygen species production. In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis only if adipose tissue lipid storage capacity is preserved.

Sarcopoterium spinosum Inhibited the Development of Non-Alcoholic Steatosis and Steatohepatitis in Mice

“…Insulin resistance increases hepatic lipogenesis via several mechanisms. Systemic insulin resistance increased adipose tissue lipolysis, leading to an increased flux of FFAs, the substrate for lipogenesis, to the liver [27]. In addition, insulin resistance is paradoxically associated with an elevated rate of de novo lipogenesis.…”

Interorgan Metabolic Crosstalk in Human Insulin Resistance

“…Several questions remain unanswered: The impact of the subcellular localization of DAG for hepatic PKC activation in humans is uncertain. Also, the concept that hepatic DAG may be important for inhibition of hepatic insulin signaling, while hepatic ceramides may be more relevant for the progression of NAFLD has been currently addressed in mouse models of NAFLD and in a preliminary study in humans (15,187,330).…”

The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes

“…Cell culture hSkMCs were differentiated from proliferating satellite cells and were cultured as previously described [19]. The mouse AML12 (alpha mouse liver 12) hepatocyte cell line was maintained in DMEM/F12 (Thermo Fisher Scientific, Waltham, MA, USA) for 48 h. Primary hepatocytes were isolated from male C57BL/6 mice as described [20,21]. 3T3-L1 fibroblasts were differentiated to adipocytes in Iscove's Modified Dulbecco's Medium IMDM, PAN Biotech, Aidenbach, Germany).…”