Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease

Abstract

Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes and their regulators in humans by using positional isotopomer NMR tracer analysis. Ten overweight/obese subjects received stable isotope infusions of: [D7]glucose, [13C4]β-hydroxybutyrate and [3-13C]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy (1H-MRS). The KD diet decreased IHTG by 31% in the face of a 3% decrease in body weight and decreased hepatic insulin resistance (−58%) despite an increase in NEFA concentrations (+35%). These changes were attributed to increased net hydrolysis of IHTG and partitioning of the resulting fatty acids toward ketogenesis (+232%) due to reductions in serum insulin concentrations (−53%) and hepatic citrate synthase flux (−38%), respectively. The former was attributed to decreased hepatic insulin resistance and the latter to increased hepatic mitochondrial redox state (+167%) and decreased plasma leptin (−45%) and triiodothyronine (−21%) concentrations. These data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by KD: That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.

Efficacy of a 2-Month Very Low-Calorie Ketogenic Diet (VLCKD) Compared to a Standard Low-Calorie Diet in Reducing Visceral and Liver Fat Accumulation in Patients With Obesity

“…Although one could argue that these results relate to the inequality in calorie intake between VLCKD and conventional LC diets, the differences regarding the correlation between VAT and PDFF at baseline and at 2 months between groups may indicate differently. Studies have shown that the fast reduction in liver fat is probably more related to the ketogenic state than to overall calorie restriction (17), and insulin resistance has been suggested as a key mechanism in this process (30). In a prior study, Luukkonen et al (17) have described a high rate of liver triglycerides hydrolysis during the increased hepatic production of ketones, as serum insulin concentrations, endogenous glucose production, and hepatic insulin resistance decrease in patients undergoing VLCKD.…”

“…Studies have shown that the fast reduction in liver fat is probably more related to the ketogenic state than to overall calorie restriction (17), and insulin resistance has been suggested as a key mechanism in this process (30). In a prior study, Luukkonen et al (17) have described a high rate of liver triglycerides hydrolysis during the increased hepatic production of ketones, as serum insulin concentrations, endogenous glucose production, and hepatic insulin resistance decrease in patients undergoing VLCKD. In our study, however, this relationship was not confirmed as differences in reduction of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) between both groups failed to reach statistical differences.…”

“…It is likely that the lack of statistical significance in our study is related to the small sample size, however conceivable that the reduction in VAT and liver fat fraction in such a short term in patients undergoing VLCKD is also related to additional metabolic changes. Most studies to date examining the relationship between NAFLD and insulin resistance are cross-sectional in design, have small sample sizes, or use rat models (17,(31)(32)(33)(34)(35)(36)(37)(38), and hence, future longitudinal clinical studies with larger cohorts should be performed to validate the role of insulin resistance in the reversal of NAFLD at short and long terms.…”

“…Alternatively, bariatric surgery promotes effective weight loss capable of improving fat deposition in the liver and in the visceral compartment, although with some risk of surgical complications, particularly in patients with comorbidities (13)(14)(15). Very LC ketogenic diet (VLCKD) has been proposed as an effective weight loss intervention potentially suitable for the treatment of NAFLD and for the reduction of VAT, which may be beneficial to reduce the state of insulin resistance and end-organ damage (16)(17)(18).…”

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

“…Several dietary intervention strategies have been tested: modification of diet composition (for example, Mediterranean, low-carbohydrate, low-fat, and ketogenic diets) or feeding behavior (time-restricted feeding or intermittent fasting) with the Mediterranean diet showing the most promising results for reducing hepatic steatosis, dyslipidemia, and other metabolic comorbidities (reviewed by Saeed et al) [ 119 ]. A recent study of overweight and obese patients showed that consumption of a ketogenic diet reduced intrahepatic fat content (measured by MRS) and markedly increased hepatic mitochondrial activity [ 120 ]. This was paralleled by a 25% reduction in plasma TG levels and improved insulin sensitivity despite minimal (∼3%) weight loss.…”