Hepatic VLDL Overproduction: Is Hyperinsulinemia or Insulin Resistance the Culprit?

Abstract

The mechanism behind raised triglyceride levels in those with insulin resistance and diabetes remains intriguing. The question as to whether chronic hyperinsulinemia increaseshepaticvery low-density lipoprotein(VLDL)production—the predominant contributor to circulating triglyceride levels—is a difficult one to address experimentally. Acute insulin infusion reduces production of VLDL-apolipoprotein B (apoB), particularly in the large triglyceride-rich VLDL1 fraction, in healthy nonobese adults (1–4); however, this suppressive effect of insulin is attenuated or lost in the insulin-resistant conditions of obesity (3) or type 2 diabetes (4). Insulin resistance (a condition characterized by chronic elevations in circulating insulin concentrations) is also associated with increased VLDL-apoB production, again principally in the VLDL1 fraction (5–7). However, in humans, becausechronichyperinsulinemiaand insulin resistancegenerally occur together, it is difficult to disentangle whether it is chronic hyperinsulinemia per se, which leads to increased hepatic VLDL production by overcoming the normally suppressive acute effect of insulin on VLDL production, or whether insulin resistance is the culprit. In vitro experiments can be potentially revealing in this regard. Acutely, insulin can suppress hepatic VLDL production by a number of mechanisms, including the downregulation of hepatic microsomal triglyceride transfer protein gene expression (8), increasing degradation of apoB within hepatocytes (9) and inhibiting the maturation of VLDL by suppressing the transfer of cytosolic triglyceride to pre-VLDL particles (10). However, the suppressive effect of insulin on VLDL production in hepatocytes has been shown to be markedly attenuated (11) or even reversed (12) when exposure to insulin is prolonged. These data would support a role for chronic hyperinsulinemia per se in mediating increased VLDL production in insulinresistant conditions. On the other hand, hepatic insulin resistance would also act to diminish any suppressive effect of insulin on VLDL production in insulin-resistant individuals. Furthermore, insulin resistance of adipose tissue leads to higher circulating nonesterified fatty acid (NEFA) concentrations, and an increased fatty acid flux to the liver can stimulate VLDL production (13); this is a systemic effect, which cannot be determined from in vitro hepatocyte preparations. Thus, whereas providing important mechanistic information, the relative importance of hyperinsulinemia vs. insulin resistance in mediating increased VLDL production in conditions of human insulin resistance cannot be fully elucidated from experiments in cell lines alone. A further issue to consider is the potential role of hyperinsulinemia in mediating hepatic steatosis. Fatty liver is present in a large proportion of type 2 diabetes patients (14) and nondiabetic obese individuals (15)—it is present in almost 100% of obese diabetic patients (14)—and liver fat content correlates strongly with both hepatic VLDL1apoB and VLDL1-triglyceride production rates (16). Recent reviews have hypothesized that hyperinsulinemia could play a causal role in mediating hepatic steatosis through up-regulation of de novo lipogenesis (17, 18). Thus, hyperinsulinemia could indirectly facilitate VLDL overproduction by promoting liver fat accumulation. However, the relative contribution of insulin-mediated de novo lipogenesis vs. other mechanisms driving hepatic steatosis remains open to debate, with peripheral insulin resistance (17, 18) and chronic positive energy balance (17), particularly excess carbohydrate consumption (19), potentially playing more important roles.