Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the leading cause of advanced liver disease in Western countries. NAFLD is defined in the presence of increased hepatic fat content, which is mainly stored under the form of neutral lipids within intracellular droplets and is not explained by at risk alcohol intake. In order to understand the pathogenesis, monitor the progression and find novel treatments for this condition, previous research efforts mainly addressed the role of inflammation. However, very recent data seem to suggest that hepatic lipid accumulation may be involved in NAFLD pathogenesis by driving secondary inflammation and fibrosis progression. Here, we will briefly review the novel results derived from natural history, genetics, imaging studies and therapeutic trials that support the notion that hepatic fat accumulation may represent a major clinical outcome and therapeutic target for NAFLD. Indeed, prospective and genetic data are consistent with hepatic fat being a driver of NAFLD progression. Furthermore, new technologies will render possible to monitor hepatic fat content without the need of invasive assessment, thereby allowing to identify patients at higher risk, and to monitor the response to drugs that act by decreasing hepatic lipid accumulation.

Randomized trial comparing effects of weight loss by liraglutide with lifestyle modification in non‐alcoholic fatty liver disease

“…Non‐alcoholic fatty liver disease (NAFLD), defined as accumulation of excess fat in the liver, is increasing in prevalence worldwide in association with rising obesity rates to become the most common cause of chronic liver disease in the world, afflicting 25% of the global population . Hepatic lipid accumulation is a key driver of NAFLD progression to non‐alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma through inflammation and fibrosis and represents a major therapeutic target for NAFLD . Structured weight‐loss programmes which include frequent contact with healthcare providers are recommended but can be difficult to sustain because of inadequate time and effort and metabolic adaptations which oppose weight loss .…”

“…Hepatic lipid accumulation is a key driver of NAFLD progression to non‐alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma through inflammation and fibrosis and represents a major therapeutic target for NAFLD . Structured weight‐loss programmes which include frequent contact with healthcare providers are recommended but can be difficult to sustain because of inadequate time and effort and metabolic adaptations which oppose weight loss . A meta‐analysis of 80 controlled weight‐loss intervention studies found a mean attrition rate of 31%, while less than 40% of attendees adhered to unsupervised diet and exercise programmes for 3‐12 months …”

“…Weight loss and maintenance are currently the mainstays of long‐term management of NAFLD . However, weight maintenance is challenging, with weight regain of ~55% at 4‐18 months in clinical trials .…”

“…Structured weight-loss programmes which include frequent contact with healthcare providers are recommended [1][2][3][4][5] but can be difficult to sustain because of inadequate time and effort 2,3,6 and metabolic adaptations which oppose weight loss. 6 A meta-analysis of 80 controlled weight-loss intervention studies found a mean attrition rate of 31%, 7 while less than 40% of attendees adhered to unsupervised diet and exercise programmes for 3-12 months.…”

HSD17B13 as a promising therapeutic target against chronic liver disease

“…In brief, the role of HSD17B13 in human physiology and the molecular mechanism behind the genetic protection are far from being clear. The interplay between HSD17B13 and PNPLA3 is a further complicating issue, especially given that PNPLA3 itself is a potential target for therapeutic inhibition in the context of FLD . It will be important to determine what proportion of the protective effect of the HSD17B13 variant is mediated by PNPLA3 downregulation.…”