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. 2011 Aug;60(8):2011-7.
doi: 10.2337/db11-0231.

The metabolically benign and malignant fatty liver

Norbert Stefan  1 , Hans-Ulrich Häring
Affiliations

The metabolically benign and malignant fatty liver

Norbert Stefan et al. Diabetes. 2011 Aug.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Pathways involved in inflammation and metabolism in human fatty liver disease. Abundant levels of glucose, fructose, and free fatty acids directly, and fatty acids and lipopolysaccharides (LPSs) via TLR2 and 4 signaling, induce ER stress. Fatty acids and free cholesterol are also thought to induce mitochondrial dysfunction and increase ROS production. This results in the activation of inflammatory pathways involving JNK and IKK, which then induce the transcription of inflammatory cytokines and consequently play a role in the inhibition of insulin signaling via IRS1 and 2. By increasing hepatic de novo lipogenesis (DNL), fatty acids, glucose, and fructose increase the DAG pool which, through activation of PKCs, also impairs insulin signaling. IR, insulin receptor. P, phosphorylation. MD-2, myeloid differentiation protein-2.
FIG. 2.
FIG. 2.
Relationship between liver fat and insulin sensitivity in humans. There is a strong, negative relationship between liver fat content measured by 1HMR spectroscopy and insulin sensitivity estimated from the OGTT (as proposed by Matsuda and DeFronzo [10,000/√(mean insulin×mean glucose)×(fasting insulin×fasting glucose)]) after adjustment for sex, age, and total body and visceral fat mass, here shown in 337 individuals (327 without diabetes and 10 with newly diagnosed type 2 diabetes; regression line and 95% CI). However for a very similar liver fat content, individuals can be identified who are relatively insulin sensitive (green field) and insulin resistant (red field). AU, arbitrary units.
FIG. 3.
FIG. 3.
Relationships of subgroups of individuals based on liver fat and the median insulin sensitivity with liver fat, insulin sensitivity, prediabetes, and the metabolic syndrome. We measured total body and visceral fat in 337 subjects by MR tomography, and liver and intramyocellular fat by 1HMR spectroscopy. Insulin sensitivity was estimated from the OGTT (as proposed by Matsuda and DeFronzo [10,000/√(mean insulin×mean glucose)×(fasting insulin×fasting glucose)]). Participants were first divided into seven groups: quartiles of liver in subjects without fatty liver (liver fat <5.56%, n = 225) and tertiles of liver fat in subjects with fatty liver (liver fat ≥5.56%, n = 112). Each group was then divided by the median insulin sensitivity in an insulin sensitive (IS) and an insulin resistant (IR) subgroup. Within each of the seven groups, the subgroups did not differ in liver fat (all P ≥ 0.30) (A). However, insulin sensitivity (B) was lower and the prevalences of prediabetes (impaired fasting glycemia and/or impaired glucose tolerance) or newly diagnosed diabetes (C) and the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) (D) were higher in the IR compared with the IS subgroups (all P ≤ 0.0001). Arb., arbitrary.
FIG. 4.
FIG. 4.
Cause and metabolic consequences of fatty liver. Hyperglycemia and hyperinsulinemia induce hepatic de novo lipogenesis via carbohydrate response element–binding protein (ChREBP) and sterol regulatory element–binding protein (SREBP)-1c, respectively, thereby increasing the hepatic pool of fatty acyl-CoAs. This pool is also increased by augmented delivery of free fatty acids (FFAs) either through the diet or lipolysis in adipose tissue. Fatty acyl-CoAs are assembled to TAGs that remain in the liver or are secreted in the form of VLDLs. The latter pathway is regulated by several factors, among them the two enzymes SCD1 and DGAT2 as well as the microsomal transfer protein (MTP) and the availability of apoliprotein B (ApoB). ELOVL6 and PNPLA3/adiponutrin are also involved in the process of hepatic TAG storage, while specific mechanisms of action are not fully understood. Finally, a low activity of the ATGL also results in storage of fatty acyl-CoAs in the form of TAGs, thereby contributing to the detoxification of hepatic lipids. This process can also be accelerated by hepatic oxidation of fatty acyl-CoAs involving the transcription factors PPAR-α and -δ. In addition, the AMP-activated kinase (AMPK) is involved. The adipokine adiponectin stimulates FA oxidation via AMPK activation and PPAR-α induction. AMPK is also involved in the suppression of lipogenesis. When these mechanisms of detoxification are overwhelmed or not active, lipotoxicity prevails resulting in hepatic inflammation and insulin resistance. Via dysregulation of secreted hepatokines (e.g., fetuin-A, SHBG, selenoprotein P), increased glucose production and dyslipidemia, fatty liver then also induces systemic subclinical inflammation, whole-body insulin resistance, hyperglycemia, and ultimately the manifestation of type 2 diabetes and cardiovascular disease.
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