Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease.

By Gordon I. Smith, M. Shankaran, M. Yoshino, G. Schweitzer, M. Chondronikola, Joseph W. Beals, A. Okunade, B. Patterson, Edna Nyangau, T. Field and 4 more. Journal of Clinical Investigation, 2019

615 citations recorded by the source corpus.

BACKGROUND An increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in people with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear. METHODS Hepatic DNL, 24-h integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in people who were lean (n = 14), obese with normal IHTG content (Obese, n = 26) and obese with NAFLD (Obese-NAFLD, n = 27). Hepatic DNL was assessed by using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity were assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the Obese-NAFLD group were also evaluated before and after 10% diet-induced weight loss. RESULTS The contribution of hepatic DNL to IHTG-palmitate was 11%, 19% and 38% in the Lean, Obese and Obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-h plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-h plasma glucose and insulin concentrations. CONCLUSIONS These data suggest hepatic DNL is an important regulator of IHTG content, and that increases in circulating glucose and insulin stimulate hepatic DNL in people with NAFLD. Weight loss decreases IHTG content, at least in part, by decreasing hepatic DNL.

Subfields: Cardiology and Cardiovascular Medicine, Endocrinology, Diabetes and Metabolism, Epidemiology

View Paper: https://www.semanticscholar.org/paper/417f0f1960d6957d95e163a80bf7c55acefcdc32

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cardiology and Cardiovascular Medicine

1. Hannele Yki-Järvinen
2. P. Scherer
3. Amalia Gastaldelli
4. Haiming Cao
5. M. Blüher

In Endocrinology, Diabetes and Metabolism

1. Hannele Yki-Järvinen
2. S. Klein
3. Amalia Gastaldelli

In Epidemiology

1. Hannele Yki-Järvinen
2. P. Scherer
3. S. Klein
4. Amalia Gastaldelli
5. Haiming Cao
6. M. Blüher

Citations in the corpus

• Why Does Obesity Cause Diabetes? (2022, background): “Even people with a genetic variant of the patatin-like phospholipase domain-containing 3 gene, which markedly increases the risk of NAFLD, are unlikely to develop hepatic steatosis in the absence of obesity and concomitant insulin resistance (Stender et al., 2017).”
• Trends in insulin resistance: insights into mechanisms and therapeutic strategy (2022, background): “Lipotoxic injury appears to occur in response to excessive levels of serum free fatty acids (FFAs) in hepatocytes.314 Circulating FFAs are the primary causes of liver fat accumulation in MAFLD that mainly occur due to lipolysis of adipose tissues, and partially from excess lipoprotein.315 Patients w”