Hepatic Steatosis as a Marker of Metabolic Dysfunction

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal.

Keywords: NAFLD; VLDL secretion; fatty acid metabolism; glucose metabolism; insulin resistance; lipid metabolism; lipolysis; liver steatosis; nonalcoholic fatty liver disease; obesity.

Figure 1

NAFLD as a marker of metabolic dysfunction. Metabolically-normal (n = 12) and metabolically-abnormal (n = 8) obese people, defined as having low or high intrahepatic triglyceride (IHTG) content, respectively, but matched on body mass index (BMI) and fat mass, were prescribed a hypercaloric diet for 7–8 weeks, until they gained ~6% of their initial body weight. Hepatic insulin sensitivity (top panel) and skeletal muscle insulin sensitivity (bottom panel), determined by using a two-stage hyperinsulinemic-euglycemic clamp, decreased after weight gain in metabolically-abnormal but not in metabolically-normal people, suggesting that low liver fat “protects” against the adverse metabolic effects of moderate weight gain. Drawn with data provided in reference [34]. Values for insulin-mediated suppression of glucose rate of appearance (Ra) are means ± SEMs, and those for insulin-mediated stimulation of glucose rate of disappearance (Rd) are back-log-tra nsformed means with 95% confidence intervals. Hepatic and muscle insulin sensitivity were greater and IHTG content was lower in metabolically-normal than in metabolically-abnormal people, both before and after weight gain, whereas BMI and fat mass were not different. * Value after weight gain is significantly different from corresponding value before weight gain. ^† Change induced by weight gain (in absolute terms) is greater in metabolically-abnormal than in metabolically-normal people.

Figure 2

Mechanisms of metabolic dysfunction in NAFLD. Nonalcoholic fatty liver disease (NAFLD) is associated with increased release of free fatty acids (FFA) from adipose tissue, because of enlarged fat stores and the inability of insulin to down-regulate lipolysis (i.e., adipose tissue insulin resistance); systemic plasma FFA are subsequently taken up by the liver at increased rates. Intrahepatic fatty acid availability is further augmented by increased hepatic de novo lipogenesis (DNL). Increased availability of fatty acids in the liver results in accumulation of intrahepatic triglyceride (TG) and steatosis, oversecretion of very low density lipoprotein (VLDL) TG and various form of dyslipidemia, and increased glucose production (i.e., hepatic insulin resistance). Increased availability of fatty acids in muscle results in decreased glucose uptake (i.e., skeletal muscle insulin resistance). The net result of increased glucose production and decreased glucose uptake is an increase in plasma glucose concentration (hyperglycemia), which stimulates the pancreas to secrete more insulin, to compensate for the impaired insulin action. Hyperglycemia and hyperinsulinemia further augment hepatic de novo lipogenesis.