Nonalcoholic Fatty Liver Disease: Lipids and Insulin Resistance

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Key points

  • Obesity is the increased accumulation of fat (ie, triglycerides [TG]), which are synthesized from glycerol and long chain fatty acids (LCFA) throughout the body.

  • LCFA enter adipocytes, hepatocytes, and cardiomyocytes via specific, facilitated transport processes, which are regulated in obesity at least in part by insulin, leptin, and spexin.

  • In obesity, metabolism of the increased cellular TG content may lead to cell-specific lipotoxicity, contributing to comorbidities such as nonalcoholic fatty

Fatty acids, triglycerides, and nonalcoholic fatty liver disease pathophysiology

Most NAFLD in the Western world evolves on a background of obesity. Obesity is the increased accumulation of fat (ie, triglycerides [TG]), synthesized from glycerol and long-chain fatty acids (LCFA), throughout the body. TG are stored in large lipid droplets in adipocytes and smaller droplets in parenchymal cells, notably hepatocytes28, 29 and cardiomyocytes.30 In obesity, metabolism of increased TG in parenchymal cells leads to cell-specific lipotoxicity. This article therefore concentrates on

Long-chain fatty acid transport in specific disease models

At least in the Western world, there is a strong association between obesity and NAFLD. As just described, alterations in adipose tissue LCFA sequestration play an important role in the pathogenesis of obesity, and analogous alterations in hepatocellular LCFA uptake play a similar role in the excess hepatic TG accumulation characterizing SHS. However, in contrast with adipocyte LCFA transport, which has been extensively studied in both rodent and readily available human fat samples, the limited

Hepatic Steatosis

SHS and other stages of NAFLD commonly accompany obesity. More than half of all obese patients have some form of NAFLD; ∼ 25% have NASH, with or without significant hepatic fibrosis (eg, Refs.7, 8, 9, 94).

Future prospects

NAFLD has sparked a dramatic expansion of the literature. From mid-1995 to mid-2015, more than 8200 articles about NAFLD entered major databases. Despite improved understanding of its pathophysiology, the prevalences of NAFLD and NASH continue to increase worldwide, and the long-term effectiveness of most currently available therapies is limited,110, 111 in part because of the frequency of weight regain. For additional reviews about current and future therapies see Ganesh S, Rustgi VK: Current

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    Disclosure: The authors have nothing to disclose.

    Funding: Supported by grant #5U01DK066667-11 Revised, Bariatric Surgery: Outcomes and Impact on Pathophysiology, from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

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