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Elevated de novo lipogenesis, slow liver triglyceride turnover, and clinical correlations in nonalcoholic steatohepatitis patients.

ABSTRACT: De novo lipogenesis (DNL) converts carbon substrates to lipids. Increased hepatic DNL could contribute to pathogenic liver triglyceride accumulation in nonalcoholic steatohepatitis (NASH) and therefore may be a potential target for pharmacological intervention. Here, we measured hepatic DNL using heavy water in 123 patients with NASH with fibrosis or cirrhosis, calculated the turnover of hepatic triglycerides to allow repeat labeling studies, and determined the associations of hepatic DNL with metabolic, fibrotic, and imaging markers. We found that hepatic DNL was higher in patients with fibrotic NASH [median (IQR), 40.7% contribution to palmitate (32.1, 47.5), n=103] than has been previously reported in healthy volunteers and remained elevated [median (IQR), 36.8% (31.0, 44.5), n=20] in patients with cirrhosis, despite lower liver fat content. We also showed that turnover of intrahepatic triglyceride pools was slow (t_½ >10 days). Furthermore, DNL contribution was determined to be independent of liver stiffness by magnetic resonance imaging but was positively associated with the number of large very low density lipoprotein (VLDL) particles, the size of VLDL, the lipoprotein insulin resistance score, and levels of ApoB100, and trended toward negative associations with the fibrosis markers FIB-4, FibroSure, and APRI. Finally, we found treatment with the acetyl-CoA carboxylase inhibitor firsocostat reduced hepatic DNL at 4 and 12 weeks, using a correction model for residual label that accounts for hepatic triglyceride turnover. Taken together, these data support an important pathophysiological role for elevated hepatic DNL in NASH and demonstrate that response to pharmacological agents targeting DNL can be correlated with pretreatment DNL.

SUBMITTER: Lawitz EJ

PROVIDER: S-EPMC9424583 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Elevated de novo lipogenesis, slow liver triglyceride turnover, and clinical correlations in nonalcoholic steatohepatitis patients.

Lawitz Eric J EJ Li Kelvin W KW Nyangau Edna E Field Tyler John TJ Chuang Jen-Chieh JC Billin Andrew A Wang Lulu L Wang Ya Y Huss Ryan S RS Chung Chuhan C Subramanian G Mani GM Myers Robert P RP Hellerstein Marc K MK

Journal of lipid research 20220711 9

De novo lipogenesis (DNL) converts carbon substrates to lipids. Increased hepatic DNL could contribute to pathogenic liver triglyceride accumulation in nonalcoholic steatohepatitis (NASH) and therefore may be a potential target for pharmacological intervention. Here, we measured hepatic DNL using heavy water in 123 patients with NASH with fibrosis or cirrhosis, calculated the turnover of hepatic triglycerides to allow repeat labeling studies, and determined the associations of hepatic DNL with m ...[more]

PMID: 35835205

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Project description:BACKGROUNDAn 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 individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed 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 a diet-induced weight loss of 10%.RESULTSThe 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-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.

Project description:BackgroundNonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with hepatic morbidity and mortality and extra-hepatic comorbidities. Published NASH cost-effectiveness models (CEMs) are heterogeneous and consistently omit comorbid conditions that frequently co-exist alongside NASH. We aimed to develop a de novo CEM framework that incorporates extra-hepatic disease states and outcomes alongside hepatic components to enable future estimation of the cost-effectiveness of NASH interventions.MethodsPatient-level simulation and cohort-level Markov models were implemented in the same framework. Model inputs included fibrosis progression; late-stage liver disease outcomes; comorbidity outcomes for cardiovascular disease, type 2 diabetes, and obesity; mortality; health-related quality of life; and direct medical costs. The prototype analysis assessed the cost-effectiveness of obeticholic acid versus standard of care from a US payer perspective over a lifetime horizon with costs and effects discounted at 3% per annum. However, the CEM was designed for easy adaptation to other countries, time horizons, and other considerations. Efficacy and adverse event parameters were obtained from the 18-month interim analysis of the REGENERATE trial. Outputs include total and incremental costs, total life years, and quality-adjusted life years.ResultsIn this model, total costs, total life years, and quality-adjusted life years were all higher with obeticholic acid compared with standard of care. Cross-validation of this model with the 2016 and 2020 Institute for Clinical and Economic Review models revealed marked differences, mainly driven by mortality inputs, transition probability estimates, and incorporation of the effect of treatment and comorbidities.ConclusionThis is the first CEM in NASH to incorporate the clinical consequences of several comorbidities. The flexible yet standardized framework permits estimation of the cost-effectiveness of NASH interventions in a variety of settings. The model currently includes several assumptions and will be further developed as more relevant data become available.

Project description:Background & aimsThere have been few studies of the role of de novo lipogenesis in the development of nonalcoholic fatty liver disease (NAFLD). We used isotope analyses to compare de novo lipogenesis and fatty acid flux between subjects with NAFLD and those without, matched for metabolic factors (controls).MethodsWe studied subjects with metabolic syndrome and/or levels of alanine aminotransferase and aspartate aminotransferase >30 mU/L, using magnetic resonance spectroscopy to identify those with high levels (HighLF, n = 13) or low levels (LowLF, n = 11) of liver fat. Clinical and demographic information was collected from all participants, and insulin sensitivity was measured using the insulin-modified intravenous glucose tolerance test. Stable isotopes were administered and gas chromatography with mass spectrometry was used to analyze free (nonesterified) fatty acid (FFA) and triacylglycerol flux and lipogenesis.ResultsSubjects with HighLF (18.4% ± 3.6%) had higher plasma levels of FFAs during the nighttime and higher concentrations of insulin than subjects with LowLF (3.1% ± 2.7%; P = .04 and P < .001, respectively). No differences were observed between groups in adipose flux of FFAs (414 ± 195 μmol/min for HighLF vs 358 ± 105 μmol/min for LowLF; P = .41) or production of very-low-density lipoprotein triacylglycerol from FFAs (4.06 ± 2.57 μmol/min vs 4.34 ± 1.82 μmol/min; P = .77). In contrast, subjects with HighLF had more than 3-fold higher rates of de novo fatty acid synthesis than subjects with LowLF (2.57 ± 1.53 μmol/min vs 0.78 ± 0.42 μmol/min; P = .001). As a percentage of triacylglycerol palmitate, de novo lipogenesis was 2-fold higher in subjects with HighLF (23.2% ± 7.9% vs 10.1% ± 6.7%; P < .001); this level was independently associated with the level of intrahepatic triacylglycerol (r = 0.53; P = .007).ConclusionsBy administering isotopes to subjects with NAFLD and control subjects, we confirmed that those with NAFLD have increased synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFAs and did not suppress the contribution from de novo lipogenesis on fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD.

Dataset Information

Elevated de novo lipogenesis, slow liver triglyceride turnover, and clinical correlations in nonalcoholic steatohepatitis patients.

Publications

Elevated de novo lipogenesis, slow liver triglyceride turnover, and clinical correlations in nonalcoholic steatohepatitis patients.

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